3-amino-1-arylpropyl azaindoles and uses thereof

ABSTRACT

The present invention provides compounds of the formula: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts, solvates or prodrugs thereof,
 
wherein p, Ar, R 1 , R 2 , R 3 , R a , R b , R c , R d  and R e  are defined herein. Also provided are pharmaceutical compositions, methods of using, and methods of preparing the compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to the benefit of provisional patentapplication Ser. No. 60/741,272 filed on Nov. 30, 2005, the disclosureof which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to 3-amino-1-arylpropyl substituted heteroarylcompounds and methods for using the same. In particular, compounds ofthe present invention are useful for treatment of diseases associatedwith monoamine reuptake inhibitors.

BACKGROUND OF THE INVENTION

Monoamine deficiency has been long been linked to depressive, anxiolyticand other disorders (see, e.g.: Charney et al., J. Clin. Psychiatry(1998) 59, 1-14; Delgado et al., J. Clin. Psychiatry (2000) 67, 7-11;Resser et al., Depress. Anxiety (2000) 12 (Suppl 1) 2-19; and Hirschfeldet al., J. Clin. Psychiatry (2000) 61, 4-6. In particular, serotonin(5-hydroxytryptamine) and norepinephrine are recognized as keymodulatory neurotransmitters that play an important role in moodregulation. Selective serotonin reuptake inhibitors (SSRIs) such asfluoxetine, sertraline, paroxetine, fluvoxamine, citalopram andescitalopram have provided treatments for depressive disorders (Masandet al., Harv. Rev. Psychiatry (1999) 7, 69-84). Noradrenaline ornorepinephrin reuptake inhibitors such as reboxetine, atomoxetine,desipramine and nortryptyline have provided effective treatments fordepressive, attention deficit and hyperactivity disorders (Scates etal., Ann. Pharmacother. (2000) 34, 1302-1312; Tatsumi et al., Eur. J.Pharmacol. (1997) 340, 249-258).

Enhancement of serotonin and norepinephrine neurotransmission isrecognized to be synergistic in the pharmacotherapy of depressive andanxiolytic disorders, in comparison with enhancement of only serotoninor norepinephrine neurotransmission alone (Thase et al., Br. J.Psychiatry (2001) 178, 234, 241; Tran et al., J. Clin.Psychopharmacology (2003) 23, 78-86). Dual reuptake inhibitors of bothserotonin and norepinephrine, such as duloxetine, milnacipran andvenlafaxine are currently under development for treatment of depressiveand anxiolytic disorders (Mallinckrodt et al., J. Clin. Psychiatry(2003) 5(1) 19-28; Bymaster et al., Expert Opin. Investig. Drugs (2003)12(4) 531-543). Dual reuptake inhibitors of serotonin and norepinephrinealso offer potential treatments for schizophrenia and other psychoses,dyskinesias, drug addition, cognitive disorders, Alzheimer's disease,obsessive-compulsive behaviour, attention deficit disorders, panicattacks, social phobias, eating disorders such as obesity, anorexia,bulimia and “binge-eating”, stress, hyperglycaemia, hyperlipidemia,non-insulin-dependent diabetes, seizure disorders such as epilepsy, andtreatment of conditions associated with neurological damage resultingfrom stroke, brain trauma, cerebral ischaemia, head injury andhaemorrhage. Dual reuptake inhibitors of serotonin and norepinephrinealso offer potential treatments for disorders and disease states of theurinary tract, and for pain and inflammation.

There is accordingly a need for compounds that are effective asserotonin reuptake inhibitors, norepinephrine reuptake inhibitors,and/or dual reuptake inhibitors of serotonin and norepinephrine, as wellas methods of making and using such compounds in the treatment ofdepressive, anxiolytic, genitourinary, and other disorders. The presentinvention satisfies these needs.

SUMMARY OF THE INVENTION

One aspect of the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,wherein:

-   -   p is 1 or 2;    -   Ar is:        -   pyrrolopyridinyl selected from the group consisting of            pyrrolopyridin-1-yl, pyrrolopyridin-2-yl, and            pyrrolopyridin-3-yl, each of which is optionally            substituted;        -   pyrrolopyridinyl N-oxide selected from the group consisting            of pyrrolopyridin-1-yl N-oxide, pyrrolopyridin-2-yl N-oxide,            and pyrrolopyridin-3-yl N-oxide, each of which is optionally            substituted; or        -   pyrrolopyrimidinyl selected from the group consisting of            pyrrolopyrimidin-5-yl, pyrrolopyrimidin-6-yl, and            pyrrolopyrimidin-7-yl, each of which is optionally            substituted;    -   R¹ is:        -   (a) aryl selected from phenyl and naphthyl, each optionally            substituted; or        -   (b) heteroaryl selected from indolyl, pyridinyl, thienyl,            furanyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl,            thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,            quinolinyl and isoquinolinyl, each optionally substituted;        -   (c) optionally substituted arylalkyl;        -   (d) optionally substituted heteroarylalkyl;        -   (e) cycloalkyl;        -   (f) cycloalkylmethyl; or        -   (g) branched alkyl;    -   R² is:        -   (a) hydrogen;        -   (b) alkyl;        -   (c) hydroxyalkyl;        -   (d) alkoxyalkyl;        -   (e) benzyl; or    -   or R² is a bond that connects the nitrogen atom to one of the        ring carbon atoms of Ar;    -   R³ is:        -   (a) hydrogen;        -   (b) alkyl;        -   (c) hydroxyalkyl;        -   (d) alkoxyalkyl;        -   (e) benzyl; or        -   (f) R² and R³ together with the nitrogen to which they are            attached may form an optionally substituted four to seven            membered ring that optionally includes an additional            heteroatom selected from N, O and S;    -   R^(a) is:        -   hydrogen;        -   fluoro; or        -   alkyl;    -   R^(b) is:        -   hydrogen;        -   alkyl;        -   hydroxy;        -   alkoxy;        -   fluoro; or        -   hydroxyalkyl;    -   or one of R² and R³ together with one of R^(a) and R^(b) and the        atoms to which they are attached may form a five or six membered        ring that optionally includes an additional heteroatom selected        from O, N and S;    -   R^(c) and R^(d) each independently is:        -   hydrogen; or        -   alkyl;        -   or R^(c) and R^(d) together form ═O, ═S, or ═NR^(f), wherein            R^(f) is hydrogen, alkyl, or —O_(g), wherein R^(g) is            hydrogen or alkyl;        -   or on of R² and R³ together with one of R^(c) and R^(d)            together with the atoms to which they are attached may form            a four to six membered ring that optionally includes an            additional heteroatom selected from O, N and S; and    -   R^(e) is hydrogen or alkyl.

The invention also provides pharmaceutical compositions, methods ofusing, and methods of preparing the aforementioned compounds.

The invention also provides pharmaceutical compositions, methods ofusing, and methods of preparing the aforementioned compounds.

The methods comprise, in certain embodiments:

reacting an azaindole a:

with an aldehyde b:

R¹—CHO  b;

in the presence of 2,2-dimethyl-[1,3]dioxane-4,6-dione, to form acompound c:

reacting the compound c with an amine d:

reducing compound e to form a compound of formula VI:

wherein one of X¹, X², X³, and X⁴ is N and the others are CH, and m, R¹,R², R³, R⁴, R⁵ and R⁶ are as defined herein.

In still other embodiments the subject methods comprise:

reacting an azaindole k

with an acrylic ester l

to form an azaindole propionic ester m

reducing azaindole propionic ester m to afford an indole propanol n

treating azaindole propanol n with methanesulfonyl chloride, followed bylithium chloride, to provide an azaindole propyl chloride o

and reacting azaindole propyl chloride o with an amine d

HNR²R³  d;

optionally in the presence of sodium iodide, to yield a compound offormula IV;

wherein one or two (e.g., X², and X⁴) of X¹, X², X³, and X⁴ are N andthe others are CH, and m, R¹, R², R³, R⁴, R⁵ and R⁶ are as definedherein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of anothercompound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.“Branched alkyl” means isopropyl, isobutyl, tert-butyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” means a moiety of the formula —OR, wherein R is an alkyl moietyas defined herein. Examples of alkoxy moieties include, but are notlimited to, methoxy, ethoxy, isopropoxy, tert-butoxy and the like.

“Alkoxyalkyl” means a moiety of the formula —R′—R″, where R′ is alkyleneand R″ is alkoxy as defined herein. Exemplary alkoxyalkyl groupsinclude, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkylcarbonyl” means a moiety of the formula —R′—R″, where R′ is oxoand R″ is alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —R′—R″, where R′ is —SO₂—and R″ is alkyl as defined herein.

“Alkylsulfonylalkyl” means a moiety of the formula R^(a)—SO₂—R^(b),where R^(a) is alkyl and R^(b) is alkylene as defined herein. Exemplaryalkylsulfonylalkyl groups include, by way of example,3-methanesulfonylpropyl, 2-methanesulfonylethyl,2-methanesulfonylpropyl, and the like.

“Alkylsulfonyloxy” means a moiety of the formula R^(a)—SO₂—O—, whereR^(a) is alkyl as defined herein.

“Antagonist” refers to a compound that diminishes or prevents the actionof another compound or receptor site.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, optionally substituted phenyl,naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl,oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl,diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl,benzodioxanyl, benzofuranyl, benzodioxolyl, benzopyranyl, benzoxazinyl,benzoxazinonyl, benzopiperidinyl, benzopiperazinyl, benzopyrrolidinyl,benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and thelike, including partially hydrogenated derivatives thereof.

“Aryloxy” means a moiety of the formula —OR, wherein R is an aryl moietyas defined herein.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Aralkoxy” means a moiety of the formula —OR, wherein R is an aralkylmoiety as defined herein.

“Azaindole” means a group of the formula

wherein one or two of any of X¹, X², X³ and X⁴ is N (aza), and theothers are carbon. “Azaindoles” may be optionally substituted, asdefined herein for heteroaryls, at position 1, 2 and 3, and at any ofpositions 4-through seven that are not nitrogen. “Azaindole” thusincludes: “pyrrolopyrimidines” of the above formula wherein X² and X⁴are N; “pyrrolopyrimidines” of the above formula wherein X¹ and X³ areN; “pyrrolopyrazines” of the above formula wherein X¹ and X⁴ are N;“pyrrolopyridines” of the above formula wherein X¹ is N;“pyrrolopyridines” of the above formula wherein X² is N;“pyrrolopyridines” of the above formula wherein X³ is N; and“pyrrolopyridines” of the above formula wherein X⁴ is N;

“Cyanoalkyl” means a moiety of the formula —R′—R″, where R′ is alkyleneas defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Cycloalkyl can optionally be substitutedwith one or more substituents, wherein each substituent is independentlyhydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, ordialkylamino, unless otherwise specifically indicated. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like,including partially unsaturated derivatives thereof.

“Cycloalkyloxy” and “cycloalkoxy”, which may be used interchangeably,mean a group of the formula —OR wherein R is cycloalkyl as definedherein. Exemplary cycloalkyloxy include cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and the like.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Cycloalkylalkyloxy” and “cycloalkylalkoxy”, which may be usedinterchangeably, mean a group of the formula —OR wherein R iscycloalkylalkyl as defined herein. Exemplary cycloalkyloxy includecyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy,cyclohexylmethoxy and the like.

“Heteroalkyl” means an alkyl radical as defined herein, including abranched C₄-C₇-alkyl, wherein one, two or three hydrogen atoms have beenreplaced with a substituent independently selected from the groupconsisting of —OR', —NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is aninteger from 0 to 2), with the understanding that the point ofattachment of the heteroalkyl radical is through a carbon atom, whereinR^(a) is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R^(b)and R^(c) are independently of each other hydrogen, acyl, alkyl,cycloalkyl, or cycloalkylalkyl; and when n is 0, R^(d) is hydrogen,alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R^(d) isalkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, ordialkylamino. Representative examples include, but are not limited to,2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl,2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl,3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl,aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, thiophenyl, furanyl, pyranyl,pyridinyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl,benzofuryl, benzofuranyl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, indazolyl, azaindolyl.pyrrolopyridine, pyrrolopyrimidine, isoindolyl, triazolyl, triazinyl,quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl,pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like,including partially hydrogenated derivatives thereof.

“Heteroarylalkyl” and “heteroaralkyl”, which may be usedinterchangeably, mean a radical-R′R^(b) where R^(a) is an alkylene groupand R^(b) is a heteroaryl group as defined herein

The terms “halo” and “halogen”, which may be used interchangeably, referto a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. Examples of haloalkoxy moieties include, butare not limited to, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy, and the like.

“Hydroxyalkyl” refers to a subset of heteroalkyl and refers inparticular to an alkyl moiety as defined herein that is substituted withone or more, preferably one, two or three hydroxy groups, provided thatthe same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, and the like.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl,pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

“Pyrrolopyrimidine” means a heteroaryl of the formula

(pyrrolo[2,3-d]pyrimidine) or

(pyrrolo[3,2-d]pyrimidine), which may be optionally substituted asdefined herein. “Pyrrolopyrimidine” is an “azaindole” as defined herein.

“Pyrrolopyridine” means a heteroaryl of the formula

(pyrrolo[2,3-b]pyridine),

(pyrrolo[2,3-c]pyridine),

(Pyrrolo[3,2-e]pyridine) or

(pyrrolo[3,2-b]pyridine), which may be optionally substituted as definedherein. “Pyrrolopyridine” is an “azaindole” as defined herein.

“Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl” (including indolyl such as indol-1-yl, indol-2-yl andindol-3-yl, 2,3-dihydroindolyl such as 2,3-dihydroindol-1-yl,2,3-dihydroindol-2-yl and 2,3-dihydroindol-3-yl, indazolyl such asindazol-1-yl, indazol-2-yl and indazol-3-yl, benzimidazolyl such asbenzimidazol-1-yl and benzimidazol-2-yl, benzofuranyl such asbenzofuran-2-yl and benzofuran-3-yl, benzothiophenyl such asbenzothiophen-2-yl and benzothiophen-3-yl, benzoxazol-2-yl,benzothiazol-2-yl, thienyl, furanyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyrazolyl and quinolinyl) ″ or “heterocyclyl”, means anaryl, phenyl, heteroaryl or heterocyclyl which is optionally substitutedindependently with one to four substituents, preferably one or twosubstituents selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl,haloalkoxy, cyano, nitro, heteroalkyl, amino, acylamino,mono-alkylamino, di-alkylamino, hydroxyalkyl, alkoxyalkyl, benzyloxy,cycloalkylalkyl, cycloalkoxy, cycloalkylalkoxy, alkylsulfonyloxy,optionally substituted thienyl, optionally substituted pyrazolyl,optionally substituted pyridinyl, morpholinocarbonyl,—(CH₂)_(q)—S(O)_(r)—R^(f); —(CH₂)_(q)—NR^(g)R^(h);—(CH₂)_(q)—C(═O)—NR^(g)R^(h); —(CH₂)_(q)—C(═O)—C(═O)—NR^(g)R^(h);—(CH₂)_(q)—SO₂NR^(g)R^(h); —(CH₂)_(q)—N(R^(f))—C(═O)—R^(i);—(CH₂)_(q)—C(═O)—R^(i); or —(CH₂)_(q)—N(R^(f))SO₂—R^(g); where q is 0 or1, r is from 0 to 2, R^(f), R^(g), and R^(h) each independently ishydrogen or alkyl, and each R′ is independently hydrogen, alkyl,hydroxy, or alkoxy.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

acid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid,benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid,ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,glutamic acid, glycolic acid, hydroxynaphtoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, muconic acid,2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinicacid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, andthe like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic or inorganicbase. Acceptable organic bases include diethanolamine, ethanolamine,N-methylglucamine, triethanolamine, tromethamine, and the like.Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

The terms “pro-drug” and “prodrug”, which may be used interchangeablyherein, refer to any compound which releases an active parent drugaccording to formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of formula I are prepared bymodifying one or more functional group(s) present in the compound offormula I in such a way that the modification(s) may be cleaved in vivoto release the parent compound. Prodrugs include compounds of formula Iwherein a hydroxy, amino, or sulfhydryl group in a compound of Formula Iis bonded to any group that may be cleaved in vivo to regenerate thefree hydroxyl, amino, or sulfhydryl group, respectively. Examples ofprodrugs include, but are not limited to, esters (e.g., acetate,formate, and benzoate derivatives), carbamates (e.g.,N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds offormula I, N-acyl derivatives (e.g. N-acetyl) N-Mannich bases, Schiffbases and enaminones of amino functional groups, oximes, acetals, ketalsand enol esters of ketone and aldehyde functional groups in compounds ofFormula I, and the like, see Bundegaard, H. “Design of Prodrugs” p 1-92,Elsevier, New York-Oxford (1985), and the like.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like.Skilled persons will know how to choose a group for the ease of removaland for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like.

The term “subject” does not denote a particular age or sex.

“Disease states” associated with serotonin and norepinephrineneurotransmission include depressive and anxiolytic disorders, as wellas schizophrenia and other psychoses, dyskinesias, drug addition,cognitive disorders, Alzheimer's disease, attention deficit disorderssuch as ADHD, obsessive-compulsive behaviour, panic attacks, socialphobias, eating disorders such as obesity, anorexia, bulimia and“binge-eating”, stress, hyperglycaemia, hyperlipidaemia,non-insulin-dependent diabetes, seizure disorders such as epilepsy, andtreatment of conditions associated with neurological damage resultingfrom stroke, brain trauma, cerebral ischaemia, head injury, haemorrhage,and disorders and disease states of the urinary tract.

“Depression” as used herein includes, but is not limited to, majordepression, long-term depression, dysthymia, mental states of depressedmood characterised by feelings of sadness, despair, discouragement,“blues”, melancholy, feelings of low self esteem, guilt and selfreproach, withdrawal from interpersonal contact, and somatic symptomssuch as eating and sleep disturbances.

“Anxiety” as used herein includes, but is not limited to, unpleasant orundesirable emotional states associated with psychophysiologicalresponses to anticipation of unreal, imagined or exaggerated danger orharm, and physical concomitants such as increased heart rate, alteredrespiration rate, sweating, trembling, weakness and fatigue, feelings ofimpending danger, powerlessness, apprehension and tension.

“Disorders of the urinary tract” or “uropathy” used interchangeably with“symptoms of the urinary tract” means the pathologic changes in theurinary tract. Examples of urinary tract disorders include, but are notlimited to, stress incontinence, urge incontinence, benign prostatichypertrophy (BPH), prostatitis, detrusor hyperreflexia, outletobstruction, urinary frequency, nocturia, urinary urgency, overactivebladder, pelvic hypersensitivity, urethritis, prostatodynia, cystitis,idiophatic bladder hypersensitivity, and the like.

“Disease states associated with the urinary tract” or “urinary tractdisease states” or “uropathy” used interchangeably with “symptoms of theurinary tract” mean the pathologic changes in the urinary tract, ordysfunction of urinary bladder smooth muscle or its innervation causingdisordered urinary storage or voiding. Symptoms of the urinary tractinclude, but are not limited to, overactive bladder (also known asdetrusor hyperactivity), outlet obstruction, outlet insufficiency, andpelvic hypersensitivity.

“Overactive bladder” or “detrusor hyperactivity” includes, but is notlimited to, the changes symptomatically manifested as urgency,frequency, altered bladder capacity, incontinence, micturitionthreshold, unstable bladder contractions, sphincteric spasticity,detrusor hyperreflexia (neurogenic bladder), detrusor instability, andthe like.

“Outlet obstruction” includes, but is not limited to, benign prostatichypertrophy (BPH), urethral stricture disease, tumors, low flow rates,difficulty in initiating urination, urgency, suprapubic pain, and thelike.

“Outlet insufficiency” includes, but is not limited to, urethralhypermobility, intrinsic sphincteric deficiency, mixed incontinence,stress incontinence, and the like.

“Pelvic Hypersensitivity” includes, but is not limited to, pelvic pain,interstitial (cell) cystitis, prostatodynia, prostatitis, vulvadynia,urethritis, orchidalgia, overactive bladder, and the like.

“Pain” means the more or less localized sensation of discomfort,distress, or agony, resulting from the stimulation of specialized nerveendings. There are many types of pain, including, but not limited to,lightning pains, phantom pains, shooting pains, acute pain, inflammatorypain, neuropathic pain, complex regional pain, neuralgia, neuropathy,and the like (Dorland's Illustrated Medical Dictionary, 28^(th) Edition,W. B. Saunders Company, Philadelphia, Pa.). The goal of treatment ofpain is to reduce the degree of severity of pain perceived by atreatment subject.

“Neuropathic pain” means the pain resulting from functional disturbancesand/or pathological changes as well as noninflammatory lesions in theperipheral nervous system. Examples of neuropathic pain include, but arenot limited to, thermal or mechanical hyperalgesia, thermal ormechanical allodynia, diabetic pain, entrapment pain, and the like.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using ISIS® version 2.2. Any open valency appearingon a carbon, oxygen or nitrogen atom in the structures herein indicatesthe presence of a hydrogen atom. For convenience, the IUPAC numbering ofthe positions of representative pyrrolopyridinyl compounds describedherein are shown by the formula

The positional numbering of pyrrolopyridinyl compounds remains the samefor compounds in which the aza substitution shown at the 7-position inthe above formula is moved to the 4-, 5- or 6-position of the aboveformula.

Pyrrolopyrimidinyl and related compounds described herein have IUPACnumbering as shown by the formulas:

Whenever a chiral carbon is present in a chemical structure, it isintended that all stereoisomers associated with that chiral carbon areencompassed by the structure.

All patents and publications identified herein are incorporated hereinby reference in their entirety.

Compounds of the Invention

The invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof,wherein:

-   -   p is 1 or 2;    -   Ar is:        -   pyrrolopyridinyl selected from the group consisting of            pyrrolopyridin-1-yl, pyrrolopyridin-2-yl, and            pyrrolopyridin-3-yl, each of which is optionally            substituted;        -   pyrrolopyridinyl N-oxide selected from the group consisting            of pyrrolopyridin-1-yl N-oxide, pyrrolopyridin-2-yl N-oxide,            and pyrrolopyridin-3-yl N-oxide, each of which is optionally            substituted; or        -   pyrrolopyrimidinyl selected from the group consisting of            pyrrolopyrimidin-5-yl, pyrrolopyrimidin-6-yl, and            pyrrolopyrimidin-7-yl, each of which is optionally            substituted;    -   R¹ is:        -   (a) aryl selected from phenyl and naphthyl, each optionally            substituted; or        -   (b) heteroaryl selected from indolyl, pyridinyl, thienyl,            furanyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl,            thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl,            quinolinyl and isoquinolinyl, each optionally substituted;        -   (c) optionally substituted arylalkyl;        -   (d) optionally substituted heteroarylalkyl;        -   (e) cycloalkyl;        -   (f) cycloalkylmethyl; or        -   (g) branched alkyl;    -   R² is:        -   (a) hydrogen;        -   (b) alkyl;        -   (c) hydroxyalkyl;        -   (d) alkoxyalkyl;        -   (e) benzyl; or    -   or R² is a bond that connects the nitrogen atom to one of the        ring carbon atoms of Ar;    -   R³ is:        -   (a) hydrogen;        -   (b) alkyl;        -   (c) hydroxyalkyl;        -   (d) alkoxyalkyl;        -   (e) benzyl; or        -   (f) R² and R³ together with the nitrogen to which they are            attached may form an optionally substituted four to seven            membered ring that optionally includes an additional            heteroatom selected from N, O and S;    -   R^(a) is:        -   hydrogen;        -   fluoro; or        -   alkyl;    -   R^(b) is:        -   hydrogen;        -   alkyl;        -   hydroxy;        -   alkoxy;        -   fluoro; or        -   hydroxyalkyl;    -   or one of R² and R³ together with one of R^(a) and R^(b) and the        atoms to which they are attached may form a five or six membered        ring that optionally includes an additional heteroatom selected        from O, N and S;    -   R^(c) and R^(d) each independently is:        -   hydrogen; or        -   alkyl;        -   or R^(c) and R^(d) together form ═O, ═S, or ═NR^(f), wherein            R^(f) is hydrogen, alkyl, or —OR^(g), wherein R^(g) is            hydrogen or alkyl;        -   or on of R² and R³ together with one of R^(c) and R^(d)            together with the atoms to which they are attached may form            a four to six membered ring that optionally includes an            additional heteroatom selected from O, N and S; and    -   R^(e) is hydrogen or alkyl.

It is to be understood that the scope of this invention encompasses notonly the various isomers which may exist but also the various mixture ofisomers which may be formed. Furthermore, the scope of the presentinvention also encompasses solvates and salts of compounds of formula I.

In certain embodiments of formula I, p is 1.

In many embodiments of formula I, R^(a) and R^(b) are hydrogen.

In certain embodiments, R^(c) and R^(d) are hydrogen.

In many embodiments of formula I, R^(e) is hydrogen.

In certain embodiments of formula I, R¹ is optionally substituted aryl,preferably optionally substituted phenyl or optionally substitutednaphthyl. Preferably, when R¹ is optionally substituted aryl, R¹ isoptionally substituted phenyl.

In certain embodiments of formula I, R¹ is optionally substitutedheteroaryl. In such embodiments R¹ is preferably optionally substitutedpyridinyl. When R¹ is optionally substituted pyridinyl, preferably R¹ isoptionally substituted pyridin-2-yl, optionally substituted pyridin-3-ylor optionally substituted pyridin-4-yl, and more specifically optionallysubstituted pyridin-2-yl or optionally substituted pyridin-3-yl.

In some embodiments of formula I, R¹ is optionally substitutedcycloalkyl. Preferably, when R¹ is cycloalkyl, R¹ is optionallysubstituted cyclohexyl.

In certain embodiments of formula I, R¹ is optionally substitutedphenyl.

In certain embodiments of formula I, R¹ is optionally substitutedpyridinyl.

In certain embodiments of formula I, R¹ is optionally substitutedcyclohexyl.

In certain embodiments of formula I, R¹ is phenyl, pyridin-3-yl,4-fluorophenyl, or cyclohexyl.

In certain embodiments of formula I, Ar is pyrrolo[2,3-b]pyridinylselected from pyrrolo[2,3-b]pyridin-1-yl, pyrrolo[2,3-b]pyridin-2-yl,and pyrrolo[2,3-b]pyridin-3-yl, each optionally substituted;pyrrolo[2,3-c]pyridinyl selected from the group consisting ofpyrrolo[2,3-c]pyridin-1-yl, pyrrolo[2,3-c]pyridin-2-yl, andpyrrolo[2,3-c]pyridin-3-yl, each optionally substituted;pyrrolo[3,2-b]pyridinyl selected from the group consisting ofpyrrolo[3,2-b]pyridin-1-yl, pyrrolo[3,2-b]pyridin-2-yl, andpyrrolo[3,2-b]pyridin-3-yl, each optionally substituted;pyrrolo[3,2-b]pyridinyl 4-oxide selected from the group consisting ofpyrrolo[3,2-b]pyridin-1-yl 4-oxide, pyrrolo[3,2-b]pyridin-2-yl 4-oxide,and pyrrolo[3,2-b]pyridin-3-yl 4-oxide, each optionally substituted;pyrrolo[3,2-c]pyridinyl selected from the group consisting ofpyrrolo[3,2-c]pyridin-1-yl, pyrrolo[3,2-c]pyridin-2-yl, andpyrrolo[3,2-c]pyridin-3-yl, each optionally substituted; orpyrrolo[2,3-d]pyrimidinyl selected from the group consisting ofpyrrolo[2,3-d]pyrimidin-5-yl, pyrrolo[2,3-d]pyrimidin-6-yl, andpyrrolo[2,3-d]pyrimidin-7-yl, each optionally substituted.

In certain embodiments of formula I, Ar is pyrrolo[2,3-b]pyridinylselected from pyrrolo[2,3-b]pyridin-1-yl, pyrrolo[2,3-b]pyridin-2-yl,and pyrrolo[2,3-b]pyridin-3-yl, each optionally substituted.

In certain embodiments of formula I, Ar is pyrrolo[2,3-c]pyridinylselected from the group consisting of pyrrolo[2,3-c]pyridin-1-yl,pyrrolo[2,3-c]pyridin-2-yl, and pyrrolo[2,3-c]pyridin-3-yl, eachoptionally substituted.

In certain embodiments of formula I, Ar is pyrrolo[3,2-b]pyridinylselected from the group consisting of pyrrolo[3,2-b]pyridin-1-yl,pyrrolo[3,2-b]pyridin-2-yl, and pyrrolo[3,2-b]pyridin-3-yl, eachoptionally substituted.

In certain embodiments of formula I, Ar is pyrrolo[3,2-b]pyridinyl4-oxide selected from the group consisting of pyrrolo[3,2-b]pyridin-1-yl4-oxide, pyrrolo[3,2-b]pyridin-2-yl 4-oxide, andpyrrolo[3,2-b]pyridin-3-yl 4-oxide, each optionally substituted.

In certain embodiments of formula I, Ar is pyrrolo[3,2-c]pyridinylselected from the group consisting of pyrrolo[3,2-c]pyridin-1-yl,pyrrolo[3,2-c]pyridin-2-yl, and pyrrolo[3,2-c]pyridin-3-yl, eachoptionally substituted.

In certain embodiments of formula I, Ar is pyrrolo[2,3-d]pyrimidinylselected from the group consisting of pyrrolo[2,3-d]pyrimidin-5-yl,pyrrolo[2,3-d]pyrimidin-6-yl, and pyrrolo[2,3-d]pyrimidin-7-yl, eachoptionally substituted.

In certain embodiments of formula I, Ar is pyrrolo[3,2-d]pyrimidinylselected from the group consisting of pyrrolo[2,3-d]pyrimidin-5-yl,pyrrolo[3,2-d]pyrimidin-6-yl, and pyrrolo[3,2-d]pyrimidin-7-yl, eachoptionally substituted.

In certain embodiments, Ar is pyrrolo[2,3-d]pyrimidin-7-yl,pyrrolo[2,3-b]pyridin-1-yl, pyrrolo[2,3-b]pyridin-3-yl,pyrrolo[3,2-b]pyridin-1-yl, pyrrolo[3,2-b]pyridin-1-yl 4-oxide,pyrrolo[3,2-c]pyridin-1-yl, pyrrolo[2,3-c]pyridin-1-yl,pyrrolo[3,2-c]pyridin-3-yl, or pyrrolo[2,3-c]pyridin-3-yl, each of whichis optionally substituted.

In many embodiments of formula I, one of R² and R³ is hydrogen and theother is alkyl, preferably methyl.

In certain embodiments of formula I: p is 1; R^(a), R^(b), R^(c), R^(d)and R^(e) are hydrogen; Ar is pyrrolopyridinyl or pyrrolopyridinylN-oxide, each of which is optionally substituted with one, two, three orfour substituents each independently selected from alkyl, alkoxy, halo,haloalkyl, haloalkoxy, cyano, alkylsulfonyloxy,—(CH₂)_(q)—S(O)_(r)R^(f); —(CH₂)_(q)—NR^(g)R^(h); or—(CH₂)_(q)—C(═O)—NR^(g)R^(h); where q is 0 or 1, r is from 0 to 2, andeach of R^(f), R^(g), and R^(h) is independently hydrogen or alkyl; R¹is phenyl, pyridinyl, or cyclohexyl, each of which is optionallysubstituted with one, two, three or four substituents each of which isindependently selected from alkyl, alkoxy, cyano, halo, haloalkyl,haloalkoxy, alkoxyalkyl or hydroxyalkyl; and one of R² and R³ ishydrogen while the other is alkyl, preferably methyl. In suchembodiments Ar may be pyrrolopyridin-1-yl, pyrrolopyridin-2-yl,pyrrolopyridin-3-yl, or N-oxide thereof, each of which is optionallysubstituted. In such embodiments, Ar is preferably pyrrolopyridin-1-yl,pyrrolopyridin-3-yl, or N-oxide thereof, each of which is optionallysubstituted, and more preferably Ar is pyrrolo[2,3-b]pyridin-1-yl,pyrrolo[2,3-b]pyridin-3-yl, pyrrolo[3,2-b]pyridin-1-yl,pyrrolo[3,2-b]pyridin-1-yl 4-oxide, pyrrolo[3,2-c]pyridin-1-yl,pyrrolo[2,3-c]pyridin-1-yl, pyrrolo[3,2-c]pyridin-3-yl, orpyrrolo[2,3-c]pyridin-3-yl, each of which is optionally substituted.

In certain embodiments of formula I: p is 1; R^(a), R^(b), R^(c), R^(d)and R^(e) are hydrogen; Ar is pyrrolopyrimidinyl optionally substitutedwith one, two, three or four substituents each independently selectedfrom alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano,alkylsulfonyloxy, —(CH₂)_(q)—S(O)_(r)R^(f); —(CH₂)_(q)—NR^(g)R^(h); or—(CH₂)_(q)—C(═O)—NR^(g)R^(h); where q is 0 or 1, r is from 0 to 2, andeach of R^(f), R^(g), and R^(h) is independently hydrogen or alkyl; R¹is phenyl, pyridinyl, or cyclohexyl, each of which is optionallysubstituted with one, two, three or four substituents each of which isindependently selected from alkyl, alkoxy, cyano, halo, haloalkyl,haloalkoxy, alkoxyalkyl or hydroxyalkyl; and one of R² and R³ ishydrogen while the other is alkyl, preferably methyl. In suchembodiments Ar may be pyrrolopyrimidin-5-yl, pyrrolopyrimidin-6-yl, orpyrrolopyrimidin-7-yl, each of which is optionally substituted. In suchembodiments Ar is preferably pyrrolopyrimidin-5-yl orpyrrolopyrimidin-7-yl, each of which is optionally substituted, and morepreferably Ar is optionally substituted pyrrolo[2,3-d]pyrimidin-7-yl.

In certain embodiments of formula I where p is 1 and R^(a), R^(b),R^(c), R^(d) and R^(e) are hydrogen, the subject compounds may berepresented by formula II:

wherein:

R² and R³ each independently is hydrogen or alkyl; and

Ar and R¹ are as defined herein.

In certain embodiments of formula II, one of R² and R³ is hydrogen andthe other is alkyl, preferably methyl.

In certain embodiments of formula II, R¹ is optionally substituted aryl,preferably optionally substituted phenyl or optionally substitutednaphthyl.

In certain embodiments of formula II, R¹ is optionally substitutedheteroaryl. In such embodiments, R¹ may be optionally substitutedpyridinyl. When R¹ is optionally substituted pyridinyl, preferably R¹ isoptionally substituted pyridin-2-yl, optionally substituted pyridin-3-ylor optionally substituted pyridin-4-yl, and more specifically optionallysubstituted pyridin-2-yl or optionally substituted pyridin-3-yl.

In certain embodiments of formula II, R¹ is optionally substitutedcycloalkyl. In such embodiments, R¹ is optionally substitutedcyclohexyl.

In certain embodiments of formula II, R¹ is optionally substitutedphenyl, optionally substituted pyridinyl, or optionally substitutedcyclohexyl.

In certain embodiments of formula II, R¹ is optionally substitutedphenyl.

In certain embodiments of formula II, R¹ is optionally substitutedpyridinyl.

In certain embodiments of formula II, R¹ is optionally substitutedcyclohexyl.

In certain embodiments of formula II, R¹ is phenyl, pyridin-3-yl,4-fluorophenyl, or cyclohexyl.

In certain embodiments of formula II, Ar is pyrrolo[2,3-b]pyridinylselected from pyrrolo[2,3-b]pyridin-1-yl, pyrrolo[2,3-b]pyridin-2-yl,and pyrrolo[2,3-b]pyridin-3-yl, each optionally substituted;pyrrolo[2,3-c]pyridinyl selected from the group consisting ofpyrrolo[2,3-c]pyridin-1-yl, pyrrolo[2,3-c]pyridin-2-yl, andpyrrolo[2,3-c]pyridin-3-yl, each optionally substituted;pyrrolo[3,2-b]pyridinyl selected from the group consisting ofpyrrolo[3,2-b]pyridin-1-yl, pyrrolo[3,2-b]pyridin-2-yl, andpyrrolo[3,2-b]pyridin-3-yl, each optionally substituted;pyrrolo[3,2-b]pyridinyl 4-oxide selected from the group consisting ofpyrrolo[3,2-b]pyridin-1-yl 4-oxide, pyrrolo[3,2-b]pyridin-2-yl 4-oxide,and pyrrolo[3,2-b]pyridin-3-yl 4-oxide, each optionally substituted;pyrrolo[3,2-c]pyridinyl selected from the group consisting ofpyrrolo[3,2-c]pyridin-1-yl, pyrrolo[3,2-c]pyridin-2-yl, andpyrrolo[3,2-c]pyridin-3-yl, each optionally substituted; orpyrrolo[2,3-d]pyrimidinyl selected from the group consisting ofpyrrolo[2,3-d]pyrimidin-5-yl, pyrrolo[2,3-d]pyrimidin-6-yl, andpyrrolo[2,3-d]pyrimidin-7-yl, each optionally substituted.

In certain embodiments of formula II, Ar is pyrrolo[2,3-b]pyridinylselected from pyrrolo[2,3-b]pyridin-1-yl, pyrrolo[2,3-b]pyridin-2-yl,and pyrrolo[2,3-b]pyridin-3-yl, each optionally substituted.

In certain embodiments of formula II, Ar is pyrrolo[2,3-c]pyridinylselected from the group consisting of pyrrolo[2,3-c]pyridin-1-yl,pyrrolo[2,3-c]pyridin-2-yl, and pyrrolo[2,3-c]pyridin-3-yl, eachoptionally substituted.

In certain embodiments of formula II, Ar is pyrrolo[3,2-b]pyridinylselected from the group consisting of pyrrolo[3,2-b]pyridin-1-yl,pyrrolo[3,2-b]pyridin-2-yl, and pyrrolo[3,2-b]pyridin-3-yl, eachoptionally substituted.

In certain embodiments of formula II, Ar is pyrrolo[3,2-b]pyridinyl4-oxide selected from the group consisting of pyrrolo[3,2-b]pyridin-1-yl4-oxide, pyrrolo[3,2-b]pyridin-2-yl 4-oxide, andpyrrolo[3,2-b]pyridin-3-yl 4-oxide, each optionally substituted.

In certain embodiments of formula II, Ar is pyrrolo[3,2-c]pyridinylselected from the group consisting of pyrrolo[3,2-c]pyridin-1-yl,pyrrolo[3,2-c]pyridin-2-yl, and pyrrolo[3,2-c]pyridin-3-yl, eachoptionally substituted.

In certain embodiments of formula II, Ar is pyrrolo[2,3-d]pyrimidinylselected from the group consisting of pyrrolo[2,3-d]pyrimidin-5-yl,pyrrolo[2,3-d]pyrimidin-6-yl, and pyrrolo[2,3-d]pyrimidin-7-yl, eachoptionally substituted.

In certain embodiments of formula II, Ar is pyrrolo[3,2-d]pyrimidinylselected from the group consisting of pyrrolo[2,3-d]pyrimidin-5-yl,pyrrolo[3,2-d]pyrimidin-6-yl, and pyrrolo[3,2-d]pyrimidin-7-yl, eachoptionally substituted.

In certain embodiments of formula II, Ar ispyrrolo[2,3-d]pyrimidin-7-yl, pyrrolo[2,3-b]pyridin-1-yl,pyrrolo[2,3-b]pyridin-3-yl, pyrrolo[3,2-b]pyridin-1-yl,pyrrolo[3,2-b]pyridin-1-yl 4-oxide, pyrrolo[3,2-c]pyridin-1-yl,pyrrolo[2,3-c]pyridin-1-yl, pyrrolo[3,2-c]pyridin-3-yl, orpyrrolo[2,3-c]pyridin-3-yl, each of which is optionally substituted.

In certain embodiments of formula II: Ar is pyrrolopyridinyl orpyrrolopyridinyl N-oxide, each of which is optionally substituted withone, two, three or four substituents each independently selected fromalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, alkylsulfonyloxy,—(CH₂)_(q)—S(O)_(r)R^(f); —(CH₂)_(q)—NR^(g)R^(h); or—(CH₂)_(q)—C(═O)—NR^(g)R^(h); where q is 0 or 1, r is from 0 to 2, andeach of R^(f), R^(g), and R^(h) is independently hydrogen or alkyl; R¹is phenyl, pyridinyl, or cyclohexyl, each of which is optionallysubstituted with one, two, three or four substituents each of which isindependently selected from alkyl, alkoxy, cyano, halo, haloalkyl,haloalkoxy, alkoxyalkyl or hydroxyalkyl; and one of R² and R³ ishydrogen while the other is alkyl, preferably methyl. In suchembodiments Ar may be pyrrolopyridin-1-yl, pyrrolopyridin-2-yl,pyrrolopyridin-3-yl, or N-oxide thereof, each of which is optionallysubstituted. In such embodiments, Ar is preferably pyrrolopyridin-1-yl,pyrrolopyridin-3-yl, or N-oxide thereof, each of which is optionallysubstituted, and more preferably Ar is pyrrolo[2,3-b]pyridin-1-yl,pyrrolo[2,3-b]pyridin-3-yl, pyrrolo[3,2-b]pyridin-1-yl,pyrrolo[3,2-b]pyridin-1-yl 4-oxide, pyrrolo[3,2-c]pyridin-1-yl,pyrrolo[2,3-c]pyridin-1-yl, pyrrolo[3,2-c]pyridin-3-yl, orpyrrolo[2,3-c]pyridin-3-yl, each of which is optionally substituted.

In certain embodiments of formula II: Ar is pyrrolopyrimidinyloptionally substituted with one, two, three or four substituents eachindependently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy,cyano, alkylsulfonyloxy, —(CH₂)_(q)—S(O)_(r)R^(f);—(CH₂)_(q)—NR^(g)R^(h); or —(CH₂)_(q)—C(═O)—NR^(g)R^(h); where q is 0 or1, r is from 0 to 2, and each of R^(f), R^(g), and R^(h) isindependently hydrogen or alkyl; R¹ is phenyl, pyridinyl, or cyclohexyl,each of which is optionally substituted with one, two, three or foursubstituents each of which is independently selected from alkyl, alkoxy,cyano, halo, haloalkyl, haloalkoxy, alkoxyalkyl or hydroxyalkyl; and oneof R² and R³ is hydrogen while the other is alkyl, preferably methyl.

In such embodiments Ar may be pyrrolopyrimidin-5-yl,pyrrolopyrimidin-6-yl, or pyrrolopyrimidin-7-yl, each of which isoptionally substituted. In such embodiments Ar is preferablypyrrolopyrimidin-5-yl or pyrrolopyrimidin-7-yl, each of which isoptionally substituted, and more preferably Ar is optionally substitutedpyrrolo[2,3-d]pyrimidin-7-yl.

In compounds of formula II in which Ar is optionally substitutedpyrrolo[2,3-b]pyridinyl, the subject compounds may be represented byformula III:

wherein

-   -   m is an integer from 0 to 3;    -   each of R⁴ and R⁵ is independently: hydrogen; alkoxy, cyano,        alkyl, halo, —S(O)_(r)R^(f); and —C(═O)NR^(g)R^(h); wherein r is        an integer from 0 to 2, and each of R^(f), R^(g), and R^(h) is        independently hydrogen or alkyl;    -   each R⁶ is independently: alkoxy, cyano, alkyl, amino,        alkylamino, dialkylamino, halo, —S(O)_(r)R^(f); and        —C(═O)NR^(g)R^(h); wherein r is an integer from 0 to 2, and each        of R^(f), R^(g), and R^(h) is independently hydrogen or alkyl;        and    -   R¹, R² and R³ are as defined herein.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[2,3-b]pyridin-1-yl, the compounds of the invention may be morespecifically of formula IV:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments of formula IV, the subject compounds may be morespecifically of formula IVa or IVb:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein. Preferablysuch compounds are of formula IVa.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[2,3-b]pyridin-3-yl, the compounds of the invention may be morespecifically of formula V:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments of formula V, the subject compounds may be morespecifically of formula Va or Vb:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein. Preferablysuch compounds are of formula Vb.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[2,3-c]pyridinyl, the compounds of the invention may be morespecifically of formula VI:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[2,3-c]pyridin-1-yl, the compounds of the invention may be morespecifically of formula VII:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments of formula VII, the subject compounds may be morespecifically of formula VIIa or VIIb:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein. Preferablysuch compounds are of formula VIIa.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[3,2-c]pyridinyl, the compounds of the invention may be morespecifically of formula VIII:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[3,2-c]pyridin-1-yl, the compounds of the invention may be morespecifically of formula IX:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments of formula IX, the subject compounds may be morespecifically of formula IXa or IXb:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein. Preferablysuch compounds are of formula IXa.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[3,2-b]pyridinyl, the compounds of the invention may be morespecifically of formula X:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[3,2-b]pyridin-1-yl, the compounds of the invention may be morespecifically of formula IX:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments of formula XI, the subject compounds may be morespecifically of formula XIa or XIb:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein. Preferablysuch compounds are of formula XIa.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[3,2-b]pyridinyl and R² is a bond that connects the nitrogen atomto one of the ring carbon atoms of Ar, the compounds of the inventionmay be more specifically of formula XII:

wherein m, R¹, R³, R⁴, R⁵, and R⁶ are as defined herein.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[2,3-d]pyrimidinyl, the compounds of the invention may be morespecifically of formula X:

wherein n is an integer from 0 to 2, and R¹, R², R³, R⁴, R⁵ and R⁶ areas defined herein.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[2,3-d]pyrimidin-7-yl, the compounds of the invention may be morespecifically of formula XIV:

wherein n, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments of formula XIV, the subject compounds may be morespecifically of formula XIVa or XIVb:

wherein n, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein. Preferablysuch compounds are of formula XIVa.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[3,2-b]pyridinyl N-oxide, the compounds of the invention may bemore specifically of formula XV:

wherein m, R¹, R², R³, R⁴, R⁵ and R⁶ are as defined herein.

In embodiments of formula II wherein Ar is optionally substitutedpyrrolo[3,2-b]pyridin-1-yl N-oxide, the compounds of the invention maybe more specifically of formula XVI:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein.

In certain embodiments of formula XVI, the subject compounds may be morespecifically of formula XVIa or XVIb:

wherein m, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined herein. Preferablysuch compounds are of formula XVIa.

In certain embodiments of any of formulas III-XVIb, one of R² and R³ ishydrogen and the other is alkyl, preferably methyl.

In certain embodiments of any of formulas III-XVIb, R¹ is optionallysubstituted aryl, preferably optionally substituted phenyl.

In certain embodiments of any of formulas III-XVIb, R¹ is optionallysubstituted heteroaryl. In such embodiments R¹ is preferably optionallysubstituted pyridinyl. When R¹ is optionally substituted pyridinyl,preferably R¹ is optionally substituted pyridin-2-yl, optionallysubstituted pyridin-3-yl or optionally substituted pyridin-4-yl, andmore specifically optionally substituted pyridin-2-yl or optionallysubstituted pyridin-3-yl.

In certain embodiments of any of formulas III-XVIb, R¹ is optionallysubstituted cycloalkyl, preferably optionally substituted cyclohexyl.

In certain embodiments of any of formulas III-XVIb, R¹ is phenyl,pyridinyl, or cyclohexyl, each of which is optionally substituted.

In certain embodiments of any of formulas III-XVIb, R¹ is optionallysubstituted phenyl.

In certain embodiments of any of formulas III-XVIb, R¹ is optionallysubstituted pyridinyl.

In certain embodiments of any of formulas III-XVIb, R¹ is phenyl,pyridin-3-yl, 4-fluorophenyl, or cyclohexyl.

In certain embodiments of formula III-XVIb, R⁴ is hydrogen.

In certain embodiments of formula III-XVIb, R⁵ is hydrogen.

In certain embodiments of any of formulas III-XVIb, each R⁶ isindependently halo, amino, alkylamino, dialkylamino, alkyl, cyano, oralkoxy. In these cases, R⁶ is preferably, fluoro, chloro, bromo,methoxy, cyano, isopropoxy, methylamino. More preferably, R⁶ is chloro,methoxy, isopropoxy, or methylamino.

In certain embodiments of any of formulas III-XVIb, m is 0 or 1, and R⁶is chloro, methoxy, isopropoxy, or methylamino.

In certain embodiments of any of formulas III-XVIb, m is 0 or 1, and R⁶is halo, alkyl, alkoxy or alkylamino.

In certain embodiments of any of formulas III-XVIb, m is 0.

In certain embodiments of any of formulas III-IXb, m is 1, and R⁶ ishalo, alkoxy and is located at the 4-position.

In certain embodiments of any of formulas X, XI, XIa, and XIb, m is 1,and R⁶ is alkoxy and is located at the 5- or 7-position.

In certain embodiments of any of formulas XIII, XIV, XIVa, and XIVb, mis 1, and R⁶ is alkylamino and is located at the 4-position.

In certain embodiments of formulas III-XVIb, R⁴ and R⁵ are hydrogen.

In certain embodiments of any of formulas III-XVIb, one of R⁴ and R⁵ ishydrogen and the other is alkyl, cyano, halo or alkoxy.

In certain embodiments of any of formulas III-XVIb, m is 0 or 1, R¹ isoptionally substituted phenyl, and one of R² and R³ is hydrogen and theother is alkyl, preferably methyl.

In certain embodiments of any of formulas III-XVIb, m is 0 or 1, R¹ isoptionally substituted phenyl, one of R² and R³ is hydrogen and theother is alkyl, preferably methyl, and R⁴ and R⁵ are hydrogen.

In certain embodiments of any of formulas III-XVIb, m is 0 or 1, R¹ isoptionally substituted phenyl, one of R² and R³ is hydrogen and theother is alkyl, preferably methyl, R⁴ and R⁵ are hydrogen, and each R⁶is independently halo, cyano, alkylamino, or alkoxy. In such embodimentsoptionally substituted phenyl may be phenyl optionally substituted one,two, three or four times with alkyl, alkoxy, cyano, halo, haloalkyl,haloalkoxy, alkoxyalkyl or hydroxyalkyl.

In certain embodiments of any of formulas III-XVIb, m is 0 or 1, R¹ isoptionally substituted pyridinyl, and one of R² and R³ is hydrogen andthe other is alkyl, preferably methyl. In such embodiments optionallysubstituted pyridinyl may be pyridinyl optionally substituted one, twoor three times with alkyl, alkoxy, cyano, halo, haloalkyl, haloalkoxy,alkoxyalkyl or hydroxyalkyl. In such embodiments R¹ is preferablypyridin-3-yl or pyridin-2-yl.

In certain embodiments of formulas any of III-XVIb, m is 0 or 1, R¹ isoptionally substituted cyclohexyl, one of R² and R³ is hydrogen and theother is alkyl, preferably methyl, and R⁴ and R⁵ are hydrogen. In suchembodiments optionally substituted cyclohexyl may be cyclohexyloptionally substituted one, two or three times with alkyl, alkoxy,cyano, halo, haloalkyl, haloalkoxy, alkoxyalkyl or hydroxyalkyl.

Representative compounds in accordance with the methods of the inventionare shown in Table 1.

TABLE 1 Mp (° C.) or # Structure Name (Sysname) [M + H] 1

Methyl-[7-(3-methylamino-1-phenyl- propyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-amine 296 2

Methyl-(3-phenyl-3-pyrrolo[2,3- d]pyrimidin-7-yl-propyl)-amine 267 3

Methyl-(3-phenyl-3-pyrrolo[2,3- b]pyridin-1-yl-propyl)-amine e 266 4

Methyl-[3-phenyl-3-(1H-pyrrolo[2,3- b]pyridin-3-yl)-propyl]-amine 266 5

Methyl-(3-phenyl-3-pyrrolo[3,2- b]pyridin-1-yl-propyl)-amine 93.9-95.5 6

Methyl-[3-(4-oxy-pyrrolo[3,2-b]pyridin- 1-yl)-3-phenyl-propyl]-amine 2827

[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine 300 8

[3-(5-Methoxy-pyrrolo[3,2-b]pyridin-1- yl)-3-phenyl-propyl]-methyl-amine296 9

Methyl-(3-phenyl-3-pyrrolo[3,2- c]pyridin-1-yl-propyl)-amine 266 10

[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine 158.7-159.4 11

Methyl-(3-phenyl-3-pyrrolo[2,3- c]pyridin-1-yl-propyl)-amine 266 12

Methyl-(3-pyridin-3-yl-3-pyrrolo[3,2- b]pyridin-1-yl-propyl)-amine 26713

Methyl-((S)-3-phenyl-3-pyrrolo[3,2- b]pyridin-1-yl-propyl)-amine 160-162(HCl Salt) 14

Methyl-[(R)-3-phenyl-3-(1H-pyrrolo[2,3- b]pyridin-3-yl)-propyl]-amine266 15

Methyl-[(S)-3-phenyl-3-(1H-pyrrolo[2,3- b]pyridin-3-yl)-propyl]-amine266 16

S)-6-Methyl-9-phenyl-6,7,8,9-tetrahydro- 3,6,9a-triaza-benzo[cd]azulene264 17

Methyl-[3-phenyl-3-(1H-pyrrolo[3,2- b]pyridin-3-yl)-propyl]-amine 266 18

[3-Cyclohexyl-3-(1H-pyrrolo[2,3- b]pyridin-3-yl)-propyl]-methyl-amine272 19

Methyl-[3-pyridin-3-yl-3-(1H- pyrrolo[2,3-b]pyridin-3-yl)-propyl]- amine267 20

[3-(4-Fluoro-phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-methyl-amine 284 21

[(S)-3-(7-Methoxy-pyrrolo[3,2-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine 296 22

[3-(4-Chloro-pyrrolo[2,3-b]pyridin-1-yl)- 3-phenyl-propyl]-methyl-amine300 23

[(S)-3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl- amine 71.1-72.7 (TFA Salt) 24

[(R)-3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl- amine 68.5-70.3 (TFA Salt) 25

[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propyl]-methyl- amine 297 26

Methyl-[3-phenyl-3-(1H-pyrrolo[3,2- c]pyridin-3-yl)-propyl]-amine 266 27

3-(4-Isopropoxy-1H-pyrrolo[2,3- b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine 124.0-126.5 (HCl Salt) 28

[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propyl]-methyl-amine 301 29

Methyl-[3-phenyl-3-(1H-pyrrolo[2,3- c]pyridin-3-yl)-propyl]-amine 266 30

[3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1- yl)-3-phenyl-propyl]-methyl-amine296 31

Methyl-[3-phenyl-3-(1H-pyrrolo[3,2- b]pyridin-3-yl)-propyl]-amine 266 32

[3-(R)-(4-Methoxy-1-methyl-1H- pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine 175.7-178.0 (HCl Salt) 33

[3-(S)-(4-Methoxy-1-methyl-1H- pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine 165.0-167.5 (HCl Salt) 34

3-(S)-(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl- amine 162.3-163.9 35

3-(R)-(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl- amine 160.0-161.4

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparecompounds of the invention where one of X¹, X², X³ or X⁴ is N and theothers are CH, and wherein m, R¹, R², R³, R⁴, R⁵ and R⁶ are as definedherein.

In Step 1 of Scheme A, azaindole a is treated with2,2-dimethyl-[1,3]dioxane-4,6-dione and an aldehyde b, using theprocedure of Tetrahedron 56 (2000) 5479-5492, to provide dione compoundc. Aldehyde b may comprise, for example, an aryl aldehyde such asbenzaldehyde or naphthaldehyde, a heteroaryl aldehyde such as a pyridinecarbaldehyde, thiophene carbaldehyde, furan carbaldehyde, a cycloalkylcarbaldehyde such as cyclohexanecarbaldehyde, a branched C₄-C₇-alkylcarbaldehyde, or the like, each of which may be optionally substitutedas defined herein. Numerous substituted aryl, heteroaryl, and cycloalkylaldehydes b are commercially available or are readily prepared bytechniques well known to those skilled in the art.

In step 2, the dione compound c is reacted with an amine d in thepresence of pyridine or other catalytic amine to afford an indolepropionamide compound e Amine d may comprise, for example, a monoalkylamine, a dialkyl amine, or a cyclic amine. Exemplary amines of this sortinclude ammonia, methylamine, ethylamine, isopropylamine, aniline,benzylamine, phenylethylamine, cyclopropylamine, dimethylamine,aziridine, pyrrolidine, piperidine and piperazine.

Reduction of propionamide compound e in step 3 provides a 3-aminopropylindole compound of formula X in accordance with the invention. Thisreduction may be achieved using lithium aluminum hydride, borane orborane complex, or other strong reducing agent.

Scheme B below illustrates another synthetic procedure usable to preparespecific compounds of the invention, wherein one of X¹, X², X³ or X⁴ isN and the others are CH, and m, R¹, R², R³, R⁴, R⁵ and R⁶ are as definedherein.

In step 1 of Scheme B, azaindole k is reacted with an acrylic ester l toafford an pyrrolopyridine propionic ester m. Numerous aryl, heteroaryl,cycloalkyl and branched C₄-C₇ alkyl-substituted acrylic esters 1, suchas various cinnamates, are commercially available or are readilyprepared by techniques well known to those skilled in the art and may beused in this step.

In step 2, the propionic ester m is subject to reducing conditions toprovide azaindole propanol n. This reduction may be carried out usinglithium aluminum hydride or other strong reducing agent.

The azaindole propanol n is treated with methane sulfonyl chloride instep 3, followed by lithium chloride, to provide pyrrolopyridine propylchloride o. Thionyl chloride, acyl chloride, or other chloride sourcemay alternatively be used in this step. Alternatively, treatment of nwith methane sulfonyl chloride provides the corresponding mesylatecompound (not shown).

In step 4, azaindole propyl chloride is reacted with amine d to yield a3-aminopropyl azaindole compound of formula IX in accordance with theinvention. Various amines may be used in this step as noted above inregard to Scheme A.

In Scheme C another synthetic route to the compounds of the invention isillustrated, wherein one of X¹, X², X³ or X⁴ is N and the others are CH,and m, R¹, R², R³, R⁴, R⁵ and R⁶ are as defined herein.

In Step 1 of Scheme C, substituted alkylidine Meldrum's acid compound 2is reacted with azaindole a to afford pyrrolopyridine acid g. Azaindoleacid g is treated with amine d in Step 2 to form azaindole amide r. InStep 3, azaindole amide r is reduced to yield aminopropyl azaindolecompound s, which represents some of the compounds of formula I inaccordance with the invention.

Scheme D shows another procedure for preparation of the subjectcompounds wherein X and Y are leaving group and may be the same ordifferent, one or two (e.g., X² and X⁴) of X¹, X², X³ or X⁴ is N and theothers are CH, and m, R¹, R², R³, R⁴, R⁵ and R⁶ are as defined herein.

In step 1 of Scheme D, azaindole k is reacted with alkylating agent t toafford the corresponding N-alkylated azaindole u. Compound u is thentreated with amine d to yield the corresponding aminopropyl azaindole v,which is a compound of formula I in accordance with the invention. Inmany embodiments of the procedure of Scheme D, X is OMs(methanesulfonyloxy) and Y is halo, preferably chloro.

Another route to the compounds of the invention is shown in Scheme E,wherein one of X¹, X², X³ or X⁴ is N and the others are CH, m, R¹, R²,R³, R⁴, R⁵ and R⁶ are as defined herein.

In Step 1 of Scheme E, azaindole compound a is treated with theVilsmeier reagent formed by mixing oxalyl chloride with dimethylformamide to form azaindole aldehyde w, which in turn is reacted withMeldrum's acid in Step 2 to yield azaindole compound x. Azaindole x isthen treated with Grignard reagent v in Step 3 to afford azaindolecompound z. In Step 4 compound z is reacted with amine d in the presenceof pyridine to give azaindole amide r, which is then reduced in Step 5to provide aminopropyl azaindole compound s. Compound s is one of thecompounds of formula I in accordance with the invention.

Scheme F illustrates yet another synthetic approach to the compounds ofthe invention, wherein one or two (e.g., X² and X⁴) of X¹, X², X³ or X⁴is N and the others are CH, m, R¹, R², R³, R⁴, R⁵ and R⁶ are as definedherein.

In Step 1 of Scheme F, azaindole k is reacted with mixed ester compoundaa to form a corresponding azaindole diester bb. Compound bb is treatedwith toluene sulfonic acid or like acid in Step 2 to afford thecorresponding azaindole ester compound cc. In Step 3 compound cc isreduced to give the corresponding hydroxypropyl azaindole dd. Compounddd is then treated with methanesulfonyl chloride, followed by amine d,to afford the corresponding aminopropyl azaindole v, which is a compoundof formula I in accordance with the invention.

Numerous variations on the procedures of Schemes A through F arepossible and will be readily apparent to those skilled in the art. Forexample, azaindoles a and k may be replaced by other heteroarylcompounds to provide other heteroaryl containing compounds in accordancewith the invention. The procedure of step 3 of Scheme B may be carriedout on compound X of Scheme A in embodiments where R³ is hydrogen. Theacrylic ester l used in step 1 is shown as a methyl ester. It should bereadily apparent, however, that ethyl, isopropyl or other alkyl estersmay be used in place thereof. Similarly, the methanesulfonyl chlorideutilized in step 3 may be replaced with other alkylsulfonyl or arylsulfonyl halides.

Specific details for producing compounds of the invention are describedin the Examples section below.

Utility

The compounds of the invention are usable for the treatment of diseasesor conditions associated with serotonin neurotransmission and/ornorepinephrine neurotransmission. Such diseases and conditions includedepressive and anxiolytic disorders, as well as schizophrenia and otherpsychoses, dyskinesias, drug addition, cognitive disorders, Alzheimer'sdisease, attention deficit disorders such as ADHD, obsessive-compulsivebehaviour, panic attacks, social phobias, eating disorders such asobesity, anorexia, bulimia and “binge-eating”, stress, hyperglycaemia,hyperlipidaemia, non-insulin-dependent diabetes, seizure disorders suchas epilepsy, and treatment of conditions associated with neurologicaldamage resulting from stroke, brain trauma, cerebral ischaemia, headinjury, and haemorrhage.

The compounds of the invention are also usable for treatment ofdisorders and disease states of the urinary tract such as stressincontinence, urge incontinence, benign prostatic hypertrophy (BPH),prostatitis, detrusor hyperreflexia, outlet obstruction, urinaryfrequency, nocturia, urinary urgency, overactive bladder, pelvichypersensitivity, urethritis, prostatodynia, cystitis, idiophaticbladder hypersensitivity.

The compounds of the invention also possess anti-inflammatory and/oranalgesic properties in vivo, and accordingly, are expected to findutility in the treatment of disease states associated with painconditions from a wide variety of causes, including, but not limited to,inflammatory pain, surgical pain, visceral pain, dental pain,premenstrual pain, central pain, pain due to burns, migraine or clusterheadaches, nerve injury, neuritis, neuralgias, poisoning, ischemicinjury, interstitial cystitis, cancer pain, viral, parasitic orbacterial infection, post-traumatic injuries (including fractures andsports injuries), and pain associated with functional bowel disorderssuch as irritable bowel syndrome.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. The preferred manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets preferably contain fromabout one (1) to about seventy (70) percent of the active compound.Suitable carriers include but are not limited to magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof. The abbreviations listed below may be used in the Examples.

Abbreviations

DCM dichloromethane/methylene chloride

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

EtOAc ethyl acetate

EtOH ethanol

gc gas chromatography

HMPA hexamethylphosphoramide

hplc high performance liquid chromatography

mCPBA m-chloroperbenzoic acid

MeCN acetonitrile

MeOH methanol

NMP N-methylpyrrolidinone

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

LAH lithium aluminum hydride

LDA lithium diisopropylamine

TLC thin layer chromatography

RT room temperature

Example 1N-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]amine

Step 12,2-Dimethyl-5-[phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-[1,3]dioxane-4,6-dione

To a room temperature (RT) solution of1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (Synthesis1999, 615-620) (2.88 g, 9.47 mmol) in acetonitrile (20 ml) was addedMeldrum's acid (1.5 g, 10 mmol), benzaldehyde (1.9 ml, 19 mmol)triethylamine (TEA) (1.9 ml, 14 mmol) and proline (catalytic quantity).The mixture was stirred overnight at RT, concentrated, and the residuewas partitioned between EtOAc and brine. The aqueous layer was extractedtwice with EtOAc. The organic layers were combined, dried over Na₂SO₄,filtered, concentrated, and purified via flash chromatography(hexane/EtOAc), affording2,2-dimethyl-5-[phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-[1,3]dioxane-4,6-dione.

Step 2 N-Methyl-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide

A sealed tube loaded with2,2-dimethyl-5-[phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-[1,3]dioxane-4,6-dione(700 mg), methylamine (2M in THF, 3 ml) and pyridine (5 ml) was stirredat 120° C. for 2 hours. The reaction mixture was cooled to RT andpartitioned between H₂O and EtOAc. The organic layer was separated,dried over Na₂SO₄, filtered, concentrated, and purified via flashchromatography (hexane/EtOAc) affordingN-Methyl-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide.

Step 3 N-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]amine

To a RT suspension ofN-methyl-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide (54 mg,0.19 mmol) in THF (5 ml) was added LiAlH₄ (0.38 ml, 1M in THF) at roomtemperature. The resulting mixture was refluxed for 4 h, then the sameamount of LiAlH₄ was added. The resulting mixture was refluxedovernight, cooled to RT, quenched by addition of Na₂SO₄.10H₂O. Themixture was stirred for 30 min and the solid was filtered off and washedwith EtOAc. The filtrate was concentrated and purified via flashchromatography (DCM/MeOH/NH₄OH) affordingN-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]amine as awhite foam (28 mg, 56% yield); MS M+H=266.

Step 4 Preparation and Resolution of (R)- and(S)-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-carbamicacid tert-butyl ester

To a 0° C. solution of racemicmethyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-amine (267mg, 1.01 mmol) in DCM (40 ml) was added TEA (0.47 ml, 3.37 mmol)followed by Boc₂O (416 mg, 1.91 mmol). The mixture was warmed to RT over1 hour, and then stirred at RT for 22 hours to give a racemic mixture ofMethyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-carbamic acidtert-butyl ester (not isolated). The reaction mixture was concentratedunder reduced pressure, and purified via chiral preparative HPLC bymultiple injections onto Chiralpak AD preparative 250×20 mm(hexane/i-PrOH, 6 ml/min), affording(R)-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-carbamicacid tert-butyl ester (215 mg, 31% yield) as a first fraction and(S)-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-carbamicacid tert-butyl estere (197 mg, 28% yield) as a second fraction.

Step 5 (R)- and(S)—N-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]amine

To a RT solution of(R)-methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-carbamicacid tert-butyl ester (181 mg, 0.496 mmol) in dichloromethane (DCM) (20ml) was added trifluoroacetic acid (TFA) (0.19 ml, 2.48 mmol). Themixture was stirred at RT for 24 hours then a second portion of TFA (95μl, 1.24 mmol) was added. After 24 h the mixture was concentrated, andthe residue was purified via flash chromatography (DCM/MeOH) affording(R)—N-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]amine asa TFA salt (186 mg, 76% yield, α_(D)=+20.4°)

Similarly, but starting with(S)-methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-carbamicacid tert-butyl ester,(S)—N-Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]aminewas prepared. (175 mg, 70% yield, α_(D)=−20.0°).

Example 2[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl-3-phenyl-propyl]-methyl-amine

Step 11-(tert-Butyl-dimethyl-silanyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine

To a −78° C. solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (prepared asdescribed in WO03/082289, 1.44 g, 9.47 mmol) in THF (75 ml) was slowlyadded a 1.4 M solution of n-BuLi in THF (7.4 ml). The resulting mixturewas stirred for 10 minutes, and then tert-butyl-dimethylsilyl chloride(1.4 g, 9.47 mmol) was added to the mixture. The reaction mixture waswarm to RT overnight and partitioned between H₂O and EtOAc. The organiclayer was separated, washed with brine, dried, filtered, concentrated,and purified via flash chromatography (hexane/EtOAc) affording1-(tert-Butyl-dimethyl-silanyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine as aclear oil (2.0 g, 62% yield).

Step 25-[(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione

5-[(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dionewas prepared following the procedure described for preparation of2,2-dimethyl-5-[phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-[1,3]dioxane-4,6-dionein example 1, using1-(tert-butyl-dimethyl-silanyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine.

Step 33-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamide

3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamidewas prepared (73% yield) following the procedure described forpreparation ofN-methyl-3-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide inExample 1, using5-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione.

Step 43-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl-3-phenyl-propyl]-methyl-amine

To a RT suspension of3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamide(80 mg, 0.25 mmol) in THF (3 ml) was added NaBH₄.SMe₂ (30 μl, 10M inTHF). The reaction mixture was refluxed for 2 hours, and then cooled andquenched by addition of MeOH and HCl (concentrated, 3 drops). Theresulting mixture was refluxed for 20 min, concentrated, and purifiedvia flash chromatography (DCM/MeOH/NH₄OH) affording the compound 15 as alight yellow viscous oil (23 mg, 31% yield).

Example 3[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine

Step 12-[(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic aciddiethyl ester

To a RT suspension of 4-methoxy-1H-pyrrolo[2,3-b]pyridine (prepared asdescribed in WO03/082289, 1.0 g, 6.75 mmol) in toluene (30 ml) at RT wasadded isopropyl magnesium chloride (1.5 M in THF, 4.95 ml, 7.43 mmol)dropwise. The resulting mixture was stirred at RT for 30 min and neatdiethyl benzylidene malonate (1.82 ml, 8.10 mmol) was added dropwise.The reaction was stirred for 1 h then quenched by addition of asaturated solution of NH₄Cl and diluted with H₂O and EtOAc. Theresulting white solid precipitate was filtered and dried affording2-[(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic aciddiethyl ester (2.13 g). An additional 130 mg was isolated from themother liquors, giving 85% combined yield.

Step 22-[(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic acid

To a suspension of2-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic aciddiethyl ester (1.0 g, 2.52 mmol) in a mixture of THF/EtOH (1/1, 24 ml)was added H₂O (2 ml) followed by KOH (1.41 g, 25.2 mmol). The reactionmixture was stirred at 50° C. for 4 h, and then cooled to RT andconcentrated. The solid residue was dissolved in H₂O. The resultingsolution was cooled to 0° C. and acidified to pH 4-5 by addition of HCl(1 M). The white solid precipitate was collected by filtration, washedwith cold H₂O and dried to afford2-[(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic acid(809 mg, 94% yield).

Step 3 3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propionicacid

2-[(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic acid(777 mg, 2.28 mmol) was placed in a 100 ml flask under high vacuum andheated to 160° C. The white solid melted into a orange-maroon oil andbubbling was observed. After 1 h, the reaction was cooled to RT toafford 3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propionicacid (637 mg, 94% yield).

Step 43-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamide

To a RT suspension of3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propionic acid (635mg, 2.14 mmol) in DCM (20 mL) was added TEA (0.45 mL, 3.21 mmol). Tothis mixture was added PyBOP (1.22 g, 2.35 mmol) and MeNH₂ (2 M in THF,1.60 mL, 3.21 mmol). The resulting mixture was stirred at RT for 30 min,and the white precipitate was collected by filtration to afford3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamidein 72% yield (477 mg).

Step 5[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine

To a RT suspension of3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamide(155 mg, 0.50 mmol) in THF (5 mL) was slowly added LAH (1 M in THF, 1.5mmol). The mixture was refluxed overnight, cooled to RT, and quenched byaddition of freshly ground Na₂SO₄.10H₂O. After stirring for 20 min, thesolid was filtered off and washed with EtOAc (10 mL, 3 times) and DCM(10 mL, 2 times). The filtrate was concentrated, and the residue waspurified via flash chromatography (DCM/MeOH/NH₄OH) to afford[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amineas a white solid (90 mg, 61% yield).

Step 6 Resolution of (R)- and(S)-[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine

Racemic[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-carbamicacid tert-butyl ester was prepared following the procedure of step 4 ofExample 1, and was separated by chiral preparative HPLC by multipleinjections onto a Chiralcel OD preparative column 50×500 mm(hexane/i-PrOH 80/20, 50 ml/min) to afford(R)-[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-carbamicacid tert-butyl ester (200 mg,) and(S)-[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-carbamicacid tert-butyl ester (195 mg). These compounds were deprotected usingthe procedure of step 5 of Example 1 to respectively provide(R)-[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine(216 mg, 84% yield, α_(D)=+20.4°) and(S)-[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine(208 mg, 79% yield, α_(D)=−20.5°) as trifluoroacetate salts.

Example 4 2-Pyridin-3-yl-methylene-malonic acid dimethyl ester

To a RT mixture of pyridin-3-carboxaldehyde (0.94 mL, 10 mmol) anddimethylmalonate (1.14 mL, 10.0 mmol) in benzene (30 mL) was addedpiperidine (0.10 mL, 1.0 mmol) and benzoic acid (60 mg, 0.5 mmol). Theresulting mixture was stirred at reflux overnight, cooled to RT, pouredinto water, and extracted with EtOAc. The organic layer was separated,washed with a saturated solution of NaHCO₃, dried over MgSO₄, filtered,concentrated, and purified via flash chromatography (hexanes/EtOAc) toafford 2-Pyridin-3-yl-methylene-malonic acid dimethyl ester as a whitesolid (1.90 g, 86% yield).

Example 5[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propyl]-methyl-amine

Step 12-[(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-methyl]-malonicacid dimethyl ester

A suspension of 4-methoxy-1H-pyrrolo[2,3-b]pyridine (0.5 g, 3.37 mmol)in toluene (15 ml) was cooled to 0° C., and isopropyl magnesium chloride(1.5 M in THF, 2.47 ml, 3.70 mmol) was added dropwise. The resultingmixture was stirred at RT for 30 minutes and a solution of2-(2-pyridin-3-yl-vinyl)-malonic acid dimethyl ester (867 mg, 4.04 mmol)in toluene (4 mL) was added dropwise. The reaction was stirred for 1hour, then was quenched by addition of a saturated solution of NH₄Cl.The mixture was diluted with H₂O and EtOAc, and the resulting whitesolid precipitate was collected by filtration, washed with EtOAc anddried to afford2-[(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-methyl]-malonicacid dimethyl ester in 75% yield (936 mg).

Step 23-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-propionic acid

To a RT suspension of2-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl-methyl]-malonicacid dimethyl ester (780 mg, 2.11 mmol) in THF/MeOH (20 mL, 1/1 mixture)was added water (2 mL) followed by KOH (1.18 g, 21.1 mmol). Theresulting mixture was stirred at 50° C. for 4 hours, concentrated, andthe residue was dissolved in water and acidified with HCl (1 M) to pH 4.The resulting aqueous solution was heated at reflux for 1.5 h andconcentrated. The residue was dissolved in MeOH (25 ml) and stirred for30 min at RT. The white solid precipitate was filtered off and thefiltrate was concentrated to afford3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-propionic acid.

Step 33-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-pyridin-3-yl-propionamide

To a RT solution of3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-propionic acid(627 mg, 2.11 mmol) in DMF (15 mL) was added TEA (0.44 mL, 3.16 mmol)followed by benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (1.20 g, 2.32 mmol) and MeNH₂ (2M in THF, 1.60 mL,3.16 mmol). The reaction mixture was stirred at RT for 1 h, quenchedwith H₂O, concentrated, and the residue was purified via flashchromatography (DCM/MeOH/NH₄OH) to afford the compound 26 as anoff-white foam (355 mg, 54% yield over 3 steps from the diester).

Step 4[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propyl]-methyl-amine

Following the procedure of step 5 of Example 3,[3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propyl]-methyl-aminewas prepared in 42% yield (80 mg).

Example 6Methyl-[3-pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-amine

Step 1-[Pyridin-3-yl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-malonicacid dimethyl ester

Following the procedure of step 1 of Example 5,2-[Pyridin-3-yl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-malonic aciddimethyl ester was prepared from 1H-Pyrrolo[2,3-b]pyridine in 72% yield.

Step 2 2-[Pyridin-3-yl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-malonicacid

Following the procedure of step 2 of Example 5,2-[Pyridin-3-yl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-malonic acid wasprepared from2-[Pyridin-3-yl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-malonic aciddimethyl ester, and was used without purification in the next step.

Step 3 3-Pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid

Following the procedure of step 3 of Example5,3-Pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid wasprepared and was used without purification in the next step.

Step 4N-Methyl-3-pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide

To a RT suspension of3-pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid (810 mg,3.03 mmol) in DCM (30 mL) was added TEA (0.63 mL, 4.54 mmol) followed byPyBOP (1.73 g, 3.33 mmol) and MeNH₂ (2 M in THF, 2.27 mL, 4.54 mmol).After stirring the reaction mixture at RT for 30 min, the beigeprecipitate was filtered off, and the filtrate was concentrated. Thecrude residue was purified via flash chromatography (DCM/MeOH/NH₄OH) toaffordN-Methyl-3-pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamideas a yellow oil (525 mg).

Step 5Methyl-[3-pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-amine

Methyl-[3-pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-aminewas prepared fromN-Methyl-3-pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamideusing the procedure of step 5 of Example 5, in 17% yield overall (83mg), M+H=267.

Example 7N-Methyl-[3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propyl]-amine

Step 1 1H-Pyrrolo[3,2-b]pyridin-3-carbaldehyde

A mixture of 1H-pyrrolo[3,2-b]pyridine (947 mg, 8.02 mmol),hexamethylenetetramine (1.7 g, 12 mmol) and acetic acid (7.5 mL) inwater (14 mL) was refluxed under N2 for 4 hours. The reaction mixturewas cooled to RT, concentrated, and the residue was purified via flashchromatography (DCM/MeOH/NH₄OH) affording1H-Pyrrolo[3,2-b]pyridin-3-carbaldehyde as a white solid (660 mg, 56%yield).

Step 2 2-(1H-Pyrrolo[3,2-b]pyridin-3-yl-methylene)-malonic acidtert-butyl ester methyl ester

A mixture of 1H-pyrrolo[3,2-b]pyridin-3-carbaldehyde (660 mg, 4.5 mmol),tert-butyl-methyl malonate (3.8 mL, 22.5 mmol), piperidine (0.12 mL) andacetic acid (0.12 mL) in acetonitrile (40 mL) was heated to reflux. Theresulting mixture was stirred at RT for 24 h, concentrated, and purifiedvia flash chromatography (hexane/EtOAc) affording2-(1H-Pyrrolo[3,2-b]pyridin-3-yl-methylene)-malonic acid tert-butylester methyl ester as a mixture of cis- and trans-isomers (780 mg, 57%yield).

Step 3 2-[Phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl)-methyl]-malonic acidtert-butyl ester methyl ester

To a RT solution of PhMgBr (1 M in THF, 6.5 mL) in THF (10 mL) was addeda solution of 2-(1H-pyrrolo[3,2-b]pyridin-3-yl-methylene)-malonic acidtert-butyl ester methyl ester in THF (15 mL) dropwise. After stirringthe mixture for 1 hour at RT, the reaction was quenched by addition ofwater. The diluted mixture was neutralized by addition of HCl (1 M) topH 7 and extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, concentrated, and purified viaflash chromatography (hexane/EtOAc) affording2-[Phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl)-methyl]-malonic acidtert-butyl ester methyl ester (680 mg, 69% yield).

Step 4 2-[Phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl-methyl)-malonic acidmono-methyl ester

A RT solution of2-[phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl-methyl)-malonic acid tert-butylester methyl ester (320 mg) in a mixture TFA/DCM (2/1, 9 mL) was stirredfor 1.5 h, and concentrated to give2-[Phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl-methyl)-malonic acidmono-methyl ester as a trifluoroacetate salt.

Step 5 3-Phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionic acid methylester

2-[Phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl-methyl)-malonic acidmono-methyl ester trifluoroacetate (263 mg) was placed in an open roundbottom flask and was heated to between 140° C. and 150° C. for 20 min.The black oil was cooled to RT, affording3-Phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionic acid methyl estertrifluoroacetate, which was used without purification in the next step.

Step 6 3-Phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionic acid

To a RT solution of compound 37 in MeOH (5 mL) was added NaOH (1 M inH₂O, 2 mL). The reaction mixture was stirred at RT overnight andconcentrated. The aqueous residue was acidified with HCl (1 M) untilabout pH 4 and extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated to yield3-Phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionic acid (150 mg).

Step 7 N-Methyl-3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionamide

To a RT solution of 3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionicacid (150 mg, 0.56 mmol) in DMF (2 mL) was added MeNH₂ (2 M in THF, 0.85mL, 1.7 mmol) followed bybenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(300 mg, 0.67 mmol) and TEA (0.12 mL, 0.85 mmol). The mixture wasstirred at RT for 3 h, then a saturated solution of NaHCO₃ was added,and the mixture was extracted 3 times with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, concentrated, and purified viaflash chromatography (DCM/MeOH/NH₄OH), affordingN-Methyl-3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionamide.

Step 8N-Methyl-[3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propyl]-amine

To a RT solution ofN-methyl-3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionamide (25.3mg, 0.091 mmol) in THF (5 mL) was added BH₃.SMe₂ (10 M in THF, 18 μL).The resulting mixture was refluxed for 2 h, cooled to RT, and quenchedby addition of MeOH and HCl (concentrated, 3 drops). The mixture wasthen heated at reflux for 15 min, cooled to RT, concentrated, andpurified via flash chromatography (DCM/MeOH/NH₄OH), affordingN-Methyl-[3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propyl]-amine MSM+H=266.

Example 8Methyl-[3-phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propyl]-amine

Step 1 2-[Phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic aciddiethyl ester

To a RT solution of isopropylmagnesium chloride (1.5 M in THF, 2.4 mL,3.6 mmol) in THF (10 mL) was added a solution of1H-pyrrolo[3,2-c]pyridine (350 mg, 3 mmol) in THF (3 mL), followed by asolution of ZnCl₂ in THF (1 M, 3.4 mL). After stirring the resultingmixture at 50° C. for 5 minutes, 2-benzylidene-malonic acid diethylester (1.0 mL, 4.5 mmol) was added dropwise. The mixture was stirred at50° C. for 3 h, cooled to RT, quenched by addition of a saturatedsolution of NH₄Cl, and extracted 3 times with EtOAc. The combinedextracts were dried over Na₂SO₄, filtered, concentrated, and purifiedvia flash chromatography (EtOAc), affording2-[Phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic acid diethylester (0.77 g, 70% yield).

Step 2 2-[Phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic acid

To a RT solution of2-[phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic acid diethylester (0.77 g) in EtOH (40 mL) was added NaOH (2 M in water, 15 ml). Themixture was stirred at reflux for 5 h, cooled to RT, and concentrated.The aqueous residue was acidified by addition of HCl (1 M) untildissolution. To this solution was added EtOAc resulting in precipitationof a solid, which was collected by filtration and dried, affording2-[Phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic acid (341 mg,52% yield).

Step 3 3-Phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propionic acid

2-[Phenyl-(1H-pyrrolo[3,2-c]pyridin-3-yl)-methyl]-malonic acid (341 mg,1.1 mmol) was heated to 160° C. under vacuum for 1 hour and cooled toprovide solid 3-Phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propionic acidwas used without purification in the next step.

Step 4 N-Methyl-3-phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propionamide

To a RT suspension of3-phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propionic acid (1.1 mmol) inDCM/DMF (3/2, 5 mL) was added TEA (0.23 mL, 1.7 mmol) followed by MeNH₂(2 M in THF, 0.83 mL) andbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(0.58 g, 1.3 mmol). The resulting mixture was stirred at RT overnight,diluted with an aqueous solution of NaHCO₃, and extracted with EtOAc.The combined organic layers were dried over Na₂SO₄, filtered,concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH),affordingN-Methyl-3-phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propionamide (0.16g).

Step 5 Methyl-[3-phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propyl]-amine

Methyl-[3-phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propyl]-amine wasprepared fromN-methyl-3-phenyl-3-(1H-pyrrolo[3,2-c]pyridin-3-yl)-propionamide usingthe procedure described in Example 3. The free amine was converted to abis-hydrochloride salt by addition of HCl (2M in Et₂O), (43.5 mg, 23%yield). MS M+H=266.

Example 9Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propyl]-amine

Step 1 2-[Phenyl-(1H-pyrrolo[2,3-c]pyridin-3-yl)-methyl]-malonic aciddiethyl ester

To a RT solution of 1H-pyrrolo[2,3-c]pyridine (595 mg, 5.04 mmol) in THF(20 mL) was added i-PrMgCl (1.5 M in THF, 5.0 mL, 7.6 mmol) followed byZnCl₂ (1M in Et₂O, 7.6 mL). The resulting mixture was stirred at RT for5 min then a solution of 2-benzylidene-malonic acid diethyl ester (2.2mL, 10 mmol) in THF (20 mL) was added dropwise. The mixture was stirredat RT for 1 hour, quenched by addition of a saturated solution of NH₄Cl,and extracted with EtOAc. The combined extracts were washed with brine,dried over Na₂SO₄, filtered, concentrated, and purified via flashchromatography (DCM/MeOH/NH₄OH), affording2-[Phenyl-(1H-pyrrolo[2,3-c]pyridin-3-yl)-methyl]-malonic acid diethylester (0.33 g, 18% yield).

Step 2 3-Phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propionic acid

To a RT solution of2-[phenyl-(1H-pyrrolo[2,3-c]pyridin-3-yl)-methyl]-malonic acid diethylester (0.33 g) in MeOH (30 mL) was added NaOH (2 M in water, 10 ml). Themixture was refluxed for 5 h, cooled to RT, and concentrated. Theresidue was acidified by addition of HCl (1 M) and extracted with EtOAc.The combined extracts were refluxed for 10 h, cooled to RT, andconcentrated. The residue was partitioned between water and EtOAc andextracted 3 times with EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated, affording crude3-Phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propionic acid (224 mg, 94%yield), which was used in the next step without further purification.

Step 3 N-Methyl-3-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propionamide

N-Methyl-3-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propionamide wasprepared from 3-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propionic acidusing the procedure of step 4 of Example 8, 54% yield (128 mg).

Step 4 Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propyl]-amine

Methyl-[3-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propyl]-amine wasprepared fromN-methyl-3-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)-propionamide usingthe procedure of step 5 of Example 3 and was converted to ahydrochloride salt by addition of HCl (2M in Et₂O), (81 mg, 52% yield).MS M+H=266.

Example 10[3-(4-Fluoro-phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-methyl-amine

Step 12-[(4-Fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-3-oxo-pentanoicacid ethyl ester

The 2-(4-Fluorobenzylidene)malonic acid diethyl ester used in this stepwas prepared following the procedure described in Example 4, and wasobtained in 100% yield (4.95 g).2-[(4-Fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-3-oxo-pentanoicacid ethyl ester was prepared from 2-(4-fluoro-benzylidene)-malonic aciddiethyl ester and 1H-pyrrolo[2,3-b]pyridine, using the procedure of step1 of Example 5 (66% yield, 4.3 g).

Step 23-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-propionic acid

To a RT mixture of2-[(4-fluoro-phenyl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-3-oxo-pentanoicacid ethyl ester (1 g, 2.6 mmol) in THF/EtOH (40 mL, 1/1 mixture) wasadded KOH pellets (5.2 mmol). The resulting mixture was stirred at RTfor 8 hours, then poured in to a saturated solution of NH₄Cl, andneutralized until pH 7 by addition of HCl (2 M). The resulting solutionwas extracted twice with DCM and twice with EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated. The aqueousresidue was heated to 160° C. for 1 h, cooled to RT, and purified viaflash chromatography, affording3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-propionic acidas a white solid (400 mg).

Step 3 3-(4-Fluoro-phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propan-1-ol

To a RT solution of3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-propionic acid(200 mg, 0.65 mmol) in THF (10 mL) was added lithium aluminum hydride (1M in THF, 1.65 mL).

The mixture was stirred at 60° C. overnight. The reaction was quenchedby addition of excess Na₂SO₄.10H₂O, and the resulting suspension wasfiltered. The filtrate was concentrated to provide crude3-(4-Fluoro-phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propan-1-ol inquantitative yield, which was used in the next step without furtherpurification.

Step 4[3-(4-Fluoro-phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-methyl-amine

To a 0° C. solution of3-(4-fluoro-phenyl)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propan-1-ol (188mg, 0.69 mmol) in THF (10 mL) was added TEA (125 μL, 0.90 mmol). Afterstirring the resulting mixture at 0° C. for 5 min, MsCl (59 μL, 0.76mmol) was added, and the mixture was stirred at 0° C. for additional 2h, poured into a saturated solution of NaHCO₃, and extracted twice withEtOAc (50 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated to yield a yellow oil. The resulting residuewas dissolved in MeNH₂ (33% in EtOH, 15 mL) and the half of the mixturewas transferred to a sealed tube and heated to 60° C. for 3 h. Thereaction mixture was cooled to RT, concentrated, and purified via flashchromatography affording the compound 54 (5 mg, 3% yield).

Example 11Methyl-[7-(3-methylamino-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

Step 1 Methanesulfonic acid 3-chloro-1-phenyl-propyl ester

The 3-Chloro-1-phenyl-propan-1-ol used in this step was prepared from asolution of (1,3-dichloro-propyl)-benzene (5 g, 30 mmol) in Et₂O (200mL) by adding lithium aluminum hydride (1

M in THF, 30 mL) at 0° C. over 35 minutes. After completing theaddition, the reaction was quenched at 0° C. by slow addition of freshlyground Na₂SO₄.10H₂O until no more gas evolution was observed. Theresulting mixture was stirred for 1 h, and the solid was filtered offand washed with Et₂O and EtOAc. The filtrate was concentrated, and theresidue was purified via flash chromatography (hexane/EtOAc, 8/2),affording 3-Chloro-1-phenyl-propan-1-ol (4.26 g).

To a solution of the 3-chloro-1-phenyl-propan-1-ol (1.5 g, 8.79 mmol) inDCM at 0° C. (50 mL) was added TEA (1.6 mL, 11.4 mmol) followed by MsCl(0.75 mL, 9.7 mmol). The reaction mixture was stirred 1.5 hours at 0°C., quenched with ice, and partitioned between a saturated solution ofNaHCO₃ and DCM. The organic layer was separated, washed with brine,dried over MgSO₄, filtered, and concentrated at 0° C. Themethanesulfonic acid 3-chloro-1-phenyl-propyl ester (95% crude yield,2.08 g) thus prepared was used in the next step without purification.

Step 2 4-Chloro-7-(3-chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine

To a RT solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (424 mg, 2.76mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 121 mg, 3.03mmol). The reaction mixture was stirred for 30 min at RT and then asolution of methanesulfonic acid 3-chloro-1-phenyl-propyl ester in DMF(2 mL) was added at 0° C. The resulting mixture was stirred overnight atRT and then diluted with H₂O and EtOAc. The organic layer was separated,washed 3 times with water, dried over MgSO₄, filtered, concentrated, andpurified via flash chromatography (hexane/EtOAc), affording4-Chloro-7-(3-chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine as acolorless oil (480 mg, 56% yield).

Step 3Methyl-[7-(3-methylamino-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine

A mixture of4-chloro-7-(3-chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine (168mg, 0.54 mmol) and MeNH₂ (33% in EtOH, 4 mL) was heated to about 100° C.by microwave for 1 hour. The reaction mixture was then cooled,concentrated, and purified via flash chromatography (DCM/MeOH/NH₄OH,8/2/1), affordingMethyl-[7-(3-methylamino-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amineas a light brown foam in 29% yield (48 mg).

Example 12 7-(3-Chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine

Step 1 7-(3-Chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine

A suspension of4-chloro-7-(3-chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine (150mg, 0.5 mmol) and Pd/C (10%, 50% water, 150 mg) in EtOAc (50 mL) wasstirred under H₂ atmosphere (balloon pressure) for 4 h. The reactionmixture was filtered through a celite pad, and the filter cake waswashed with EtOAc (20 mL). The filtrate was concentrated and purifiedvia flash chromatography (hexane/EtOAc), affording7-(3-Chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine (111 mg, 83%yield).

Step 2 Methyl-(3-phenyl-3-pyrrolo[2,3-d]pyrimidin-7-yl-propyl)-aminebishydrochloride salt

Methyl-(3-phenyl-3-pyrrolo[2,3-d]pyrimidin-7-yl-propyl)-amine wasprepared from 7-(3-chloro-1-phenyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine(48% yield, 48 mg), following the procedure of step 3 of Example 11.Treatment with HCl (2 M in Et₂O) afforded the correspondingbis-hydrochloride salt (52 mg). MS M+H=272.

Example 13 Methyl-(3-phenyl-3-pyrrolo[2,3-b]pyridin-1-yl-propyl)-amine

Step 1 1-(3-Chloro-1-phenyl-propyl)-1H-pyrrolo[2,3-b]pyridine

1-(3-Chloro-1-phenyl-propyl)-1H-pyrrolo[2,3-b]pyridine was prepared from1H-pyrrolo[2,3-b]pyridine by following the procedure described in steps1 and 2 of Example 11 (10% yield, 78 mg).

Synthesis of Methyl-(3-phenyl-3-pyrrolo[2,3-b]pyridin-1-yl-propyl)-amine

Methyl-(3-phenyl-3-pyrrolo[2,3-b]pyridin-1-yl-propyl)-amine was preparedfrom using 1-(3-chloro-1-phenyl-propyl)-1H-pyrrolo[2,3-b]pyridinefollowing the procedure of step 3 of Example 11 (18% yield, 11 mg), andwas with HCl (1M in Et₂O) to give the corresponding bis-hydrochloridesalt (11 mg). MS M+H=271.

Example 14 Methyl-(3-phenyl-3-pyrrolo[3,2-b]pyridin-1-yl-propyl)-amine

Step 1 1-(3-Chloro-1-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine

1-(3-Chloro-1-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine was prepared from1H-pyrrolo[3,2-b]pyridine following the procedure described in steps 1and 2 of Example 11 (66% yield, 98 mg).

Step 2 Methyl-(3-phenyl-3-pyrrolo[3,2-b]pyridin-1-yl-propyl)-amine

Methyl-(3-phenyl-3-pyrrolo[3,2-b]pyridin-1-yl-propyl)-amine was preparedfrom 1-(3-chloro-1-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine, followingthe procedure of step 3 of Example 11 (80% yield, 78 mg) as an off-whitesolid.

Example 15(S)-Methyl-(3-phenyl-3-pyrrolo[3,2-b]pyridin-1-yl-propyl)-amine

Step 1 (S) 1-(3-Chloro-1-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine

1-(3-Chloro-1-(S)-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine was preparedfrom 1H-pyrrolo[3,2-b]pyridine and 3-chloro-1-(R)-phenyl-propan-1-olfollowing the procedure described in steps 1 and 2 of Example 11 (24%yield [268 mg, α_(D)=−111.0° (MeOH, c=¹)].

Step 2 (S)-Methyl-(3-phenyl-3-pyrrolo[3,2-b]pyridin-1-yl-propyl)-amine

Methyl-(3-(S)-phenyl-3-pyrrolo[3,2-b]pyridin-1-yl-propyl)-amine wasprepared from1-(3-Chloro-1-(S)-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine, followingthe procedure of step 3 of Example 11 (76% yield, 188 mg), and wastreated with HCl (1 M in Et₂O) to afford the correspondingbis-hydrochloride salt (219 mg, 78% yield) as a white solid. MS M+H=271.

Example 16Methyl-[3-(4-oxy-pyrrolo[3,2-b]pyridin-1-yl)-3-phenyl-propyl]-amine

To a 0° C. solution of1-(3-chloro-1-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine (75 mg, 0.27mmol) in DCM (5 mL) was added m-CPBA (62 mg, 0.27 mmol). The mixture wasstirred for 1 h at 0° C., then poured into an aqueous solution ofNa₂S₂O₃ (10%, 20 mL) and extracted twice with DCM (30 mL). The combinedorganic extracts were washed with NaHCO₃ (saturated solution), driedover Na₂SO₄, filtered and concentrated. The residue was treated withMeNH₂ (33% in EtOH, 2.5 mL) by microwave at 100° C. for 1 hours. Themixture was concentrated, and the residue was purified via flashchromatography (DCM/MeOH/NH₄OH), affordingMethyl-[3-(4-oxy-pyrrolo[3,2-b]pyridin-1-yl)-3-phenyl-propyl]-amine asan off-white foam in 59% yield (45 mg).

Example 17[3-(5-Methoxy-pyrrolo[3,2-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine

Step 1 5-Methoxy-1H-pyrrolo[3,2-b]pyridine

A suspension of (5-methoxy-3-nitro-pyridin-2-yl)-acetonitrile(Maybridge, 986 mg, 5.1 mmol) and Pd/C (10%, 986 mg) in EtOH/EtOAc(95/5, 50 mL) was shaken for 6 hours under H₂ (60 PSI) in Parrapparatus. The reaction mixture was then filtered through a celite pad,and the filter cake was washed with EtOAc (20 mL). The filtrate wasconcentrated, and the residue was dissolved in EtOAc (50 mL), washedwith NaHCO₃ (saturated solution, 50 mL), dried over MgSO₄, filtered,concentrated, and purified via flash chromatography (hexane/EtOAc),affording 5-Methoxy-1H-pyrrolo[3,2-b]pyridine as a white solid (720 mg,95% yield).

Step 2 1-(3-Chloro-1-phenyl-propyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine

1-(3-Chloro-1-phenyl-propyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine wasprepared from 5-methoxy-1H-pyrrolo[3,2-b]pyridine following theprocedure of steps 1 and 2 of Example 11 (62% yield, 723 mg).

Step 3[3-(5-Methoxy-pyrrolo[3,2-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine

[3-(5-Methoxy-pyrrolo[3,2-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-aminewas prepared from1-(3-chloro-1-phenyl-propyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridinefollowing the procedure of step 3 of Example 11 (55% yield, 120 mg).

Example 18 Methyl-(3-phenyl-3-pyrrolo[3,2-c]pyridin-1-yl-propyl)-amine

Step 1 1-(3-Chloro-1-phenyl-propyl)-1H-pyrrolo[3,2-c]pyridine

1-(3-Chloro-1-phenyl-propyl)-1H-pyrrolo[3,2-c]pyridine was prepared from1H-pyrrolo[3,2-c]pyridine following the procedure of steps 1 and 2 ofExample 11 (31% yield, 220 mg).

Step 2 Methyl-(3-phenyl-3-pyrrolo[3,2-c]pyridin-1-yl-propyl)-amine

Methyl-(3-phenyl-3-pyrrolo[3,2-c]pyridin-1-yl-propyl)-amine was preparedfrom 1-(3-chloro-1-phenyl-propyl)-1H-pyrrolo[3,2-c]pyridine followingthe procedure of step 3 of Example 11 (65% yield, 115 mg) a, and wastreated with HCl (1 M in Et₂O) to give the correspondentbis-hydrochloride salt (100 mg). MS M+H=271.

Example 19 Step 1 1H-Pyrrolo[2,3-c]pyridine

A suspension of 7-chloro-1H-pyrrolo[2,3-c]pyridine (650 mg, 4.2 mmol)and Pd/C (10%, 50 mg) in EtOH (25 mL) was stirred at RT under H₂atmosphere (balloon pressure). The reaction mixture was filtered througha celite pad, and the filter cake was washed with EtOAc (10 mL). Thefiltrate was concentrated and purified via flash chromatography(DCM/MeOH/NH₄OH, 9/1/0.1), affording 1H-Pyrrolo[2,3-c]pyridine as awhite solid (380 mg, 75% yield).

Step 2 1-(3-Chloro-1-phenyl-propyl)-1H-pyrrolo[2,3-c]pyridine

1-(3-Chloro-1-phenyl-propyl)-1H-pyrrolo[2,3-c]pyridine was prepared from1H-pyrrolo[2,3-c]pyridine following the procedure of steps 1 and 2 ofExample 11 (25% yield).

Step 3 Methyl-(3-phenyl-3-pyrrolo[2,3-c]pyridin-1-yl-propyl)-amine

Methyl-(3-phenyl-3-pyrrolo[2,3-c]pyridin-1-yl-propyl)-amine was preparedfrom 1-(3-chloro-1-phenyl-propyl)-1H-pyrrolo[2,3-c]pyridine followingthe procedure of step 3 of Example 11 (75% yield, 105 mg), and wastreated with HCl (1 M in Et₂O) to give the corresponding hydrochloridesalt as a white solid (65 mg).

Example 20

Step 17-Chloro-1-(3-chloro-1-(5)-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine

7-Chloro-1-(3-chloro-1-(S)-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine wasprepared from 7-chloro-1H-pyrrolo[3,2-b]pyridine and3-chloro-1-(R)-phenyl-propan-1-ol following the procedure of steps 1 and2 of Example 11 (20% yield, 40 mg).

Step 2(S)-6-Methyl-9-phenyl-6,7,8,9-tetrahydro-3,6,9a-triaza-benzo[c,d]azulene

A RT solution of7-chloro-1-(3-chloro-1-(S)-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine (40mg, 0.13 mmol) in MeNH₂ (30% in EtOH, 2 mL) was stirred for 48 h. Themixture was concentrated, and the residue was purified via flashchromatography (DCM/MeOH/NH₄OH), affording(S)-6-Methyl-9-phenyl-6,7,8,9-tetrahydro-3,6,9a-triaza-benzo[cd]azulene(15 mg, 43% yield, α_(D)=−75° (CHCl₃, c=1.2). MS M+H=264.

Example 213-(7-Methoxy-pyrrolo[3,2-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine

Step 1 7-Methoxy-1H-pyrrolo[3,2-b]pyridine

To a RT suspension of KOMe (24 mg, 1.65 mmol) and LiOMe (12 mg, 448mmol) in xylene/t-BuOH (8/1, 13.5 mL) was added7-chloro-1H-pyrrolo[3,2-b]pyridine (900 mg, 5.9 mmol). The resultingmixture was stirred at 115° C. for 48 h, then cooled to 40° C., andslowly quenched by addition of water (50 mL). The resulting mixture wascooled to 0° C. and acidified to about pH 1 by addition of HCl. Theaqueous layer was separated and basified to about pH 7 to 8 by additionof NaOH (10%) and extracted 3 times with EtOAc (50 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered, concentrated, andpurified via flash chromatography (DCM/MeOH/NH₄OH, 9/1/0.1) affordingthe compound 78 as a white solid in 47% yield (412 mg).

Step 21-(3-Chloro-1-(S)-phenyl-propyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine

1-(3-Chloro-1-(S)-phenyl-propyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridine 79was prepared from 7-methoxy-1H-pyrrolo[3,2-b]pyridine and3-chloro-1-(R)-phenyl-propan-1-ol following the procedure of steps 1 and2 of Example 11 (33% yield, 170 mg, [α_(D)==−149° (CHCl₃, c=1)]).

Step 33-(7-Methoxy-pyrrolo[3,2-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine

[3-(7-Methoxy-pyrrolo[3,2-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-aminewas prepared from1-(3-chloro-1-(S)-phenyl-propyl)-7-methoxy-1H-pyrrolo[3,2-b]pyridinefollowing the procedure of step 3 of Example 11 (36% yield, [98 mg,α_(D)=−146.9° (CHCl₃, c=1)]).

Example 22Methyl-(3-pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propyl)-amine

Step 1 2-Pyridin-3-yl-methylene-malonic acid tert-butyl ester methylester

The 2-Pyridin-3-yl-methylene-malonic acid tert-butyl ester methyl esterused in this step was prepared from tert-butyl-methylmalonate using theprocedure of Example 4 (48% yield (3.21 g).

To a 0° C. solution of 1H-pyrrolo[3,2-b]pyridine (300 mg, 2.53 mmol) inDMF (20 mL) was added NaH (60% in mineral oil, 112 mg, 2.79 mmol). Theresulting mixture was stirred 30 min at 0° C., then2-pyridin-3-yl-methylene-malonic acid tert-butyl ester methyl ester (669mg, 2.53 mmol) was added. The mixture was stirred at RT for 2 hours,poured into water (50 mL) and extracted with EtOAc (50 mL). The organiclayer was washed 3 times with water (50 mL), dried over Na₂SO₄, filteredand concentrated to give 2-Pyridin-3-yl-methylene-malonic acidtert-butyl ester methyl ester in 71% yield (694 mg), which was used inthe next step without purification.

Step 2 3-Pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propionic acid methylester

To a RT solution of2-(pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-methyl)-malonic acidtert-butyl ester methyl ester (694 mg, 1.82 mmol) in toluene (50 mL) wasadded p-TSA (727 mg, 2.1 mmol), and the mixture was stirred at refluxfor 4 h. The mixture was then poured into a saturated solution of NaHCO₃(100 mL) and extracted with EtOAc (50 mL). The organic layer was driedover Na₂SO₄, filtered, concentrated, and purified via flashchromatography (EtOAc), affording3-Pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propionic acid methyl ester(35% yield, 183 mg).

Step 3 3-Pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propan-1-ol

To a 0° C. solution of3-pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propionic acid methyl ester(150 mg, 0.53 mmol) in THF (10 mL) was added LAH (1M in THF, 0.53 mL).The reaction mixture was stirred at RT for 2 h, and quenched by additionof freshly ground Na₂SO₄.10H₂O (1 g). The mixture was filtered through acelite pad, and the filtrate was concentrated and purified via flashchromatography (DCM/MeOH/NH₄OH, 8/2/0.1), affording3-Pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propan-1-ol (66% yield, 85mg).

Step 4 Methyl-(3-pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propyl)-amine

To a 0° C. solution of3-pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propan-1-ol (85 mg, 0.33mmol) in DCM (10 mL) was added TEA (70 μL, 0.50 mmol) followed by MsCl(30 μL, 0.37 mmol). The reaction was stirred at 0° C. for 30 min thenpoured into water (50 mL) and extracted with DCM (50 mL). The organicextracts were combined, washed with a saturated solution of NaHCO₃ (50mL), dried over Na₂SO₄, filtered and concentrated. The residue wasdissolved in MeNH₂ (33% in EtOH, 4 mL) and the mixture was heated toabout 100° C. by microwave for 30 minutes. The mixture was concentrated,and the residue was partitioned between DCM and a saturated solution ofNaHCO₃. The organic layer was separated, dried over Na₂SO₄, filtered,concentrated, and purified via flash chromatography (DCM/MeOH/NH₄OH),affordingMethyl-(3-pyridin-3-yl-3-pyrrolo[3,2-b]pyridin-1-yl-propyl)-amine (92%yield, 83 mg), which was treated with HCl (1 M in Et₂O) to give thecorrespondent hydrochloride salt as a foam (75 mg).

Example 23

Step 1 4-Chloro-1-(3-chloro-1-phenyl-propyl)-1H-pyrrolo[2,3-b]pyridine

To a RT solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.31mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 57.7 mg, 1.44mmol) followed by methanesulfonic acid 3-chloro-1-phenyl-propyl ester(326 mg, 1.31 mmol). The reaction mixture was stirred at RT overnight,poured into ice-water, and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated to yield4-Chloro-1-(3-chloro-1-phenyl-propyl)-1H-pyrrolo[2,3-b]pyridine as amixture with the cyclization product8-Chloro-3-phenyl-4,5-dihydro-3H-2a-aza-5a-azonia-acenaphthylene. Themixture was used in the next step without purification.

Step 2[3-(4-Chloro-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine

The crude mixture from the previous step was dissolved in MeNH₂ (33% inEtOH, 5 mL) and heated to 130° C. via microwave for 1 hour. The mixturewas concentrated, and the residue was purified via flash chromatography(DCM/MeOH/NH₄OH) to provide[3-(4-Chloro-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine(28 mg), which was dissolved in EtOAc and 2 equivalents of HCl (1 M inEt₂O) to give the corresponding hydrochloride salt (29 mg). MS M+H=306.

Example 24[3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine

Step 1 2-[(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-phenyl-methyl]-malonicacid tert-butyl ester methyl ester

The 2-Benzylidene-malonic acid tert-butyl ester methyl ester used inthis step was prepared from tert-butyl-methylmalonate and benzaldehydeaccording to the procedure of Example 4 (36% yield, 4.53 g).

2-[(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-phenyl-methyl]-malonic acidtert-butyl ester methyl ester was prepared from4-methoxy-1H-pyrrolo[2,3-b]pyridine (WO03/082289) and2-benzylidene-malonic acid tert-butyl ester methyl ester using theprocedure of Example 7, and was used without purification.

Step 2 3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propionic acidmethyl ester

3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propionic acid methylester was prepared from2-[(4-methoxy-pyrrolo[2,3-b]pyridin-1-yl)-phenyl-methyl]-malonic acidtert-butyl ester methyl ester using the procedure of Example 7 (677 mg).

Step 3 3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propan-1-ol

3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propan-1-ol wasprepared from3-(4-methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propionic acid methylester following the procedure of Example 7, and was used in the nextstep without purification.

Step 4 3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propionaldehyde

To a RT mixture of Dess-Martin periodane (1.69 g, 3.99 mmol) in DCM (50mL) was added3-(4-methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propan-1-ol (563 mg,2.0 mmol). The reaction was stirred at RT for 2 h and then poured in asaturated solution of NaHCO₃. The organic layer was separated, and theaqueous was extracted with a mixture DCM/EtOAc (2/1). The combinedorganic layers were dried over MgSO₄, filtered and concentrated to give3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propionaldehyde, whichwas used in the next step without further purification.

Step 5[3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine

To a RT solution of MeNH₂.HCl (2.17 g, 31.9 mmol) in MeOH (40 mL) wasadded NaOH (319 mg, 7.98 mmol). The resulting mixture was stirred for 20min. Then a solution of3-(4-methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propionaldehyde (2.0mmol) in MeOH (20 mL) was added, and the resulting mixture was stirredfor 2 h. To this solution was added NaCNBH₄ (125 mg, 2.0 mmol), and themixture was stirred for 1 h, poured into water, and extracted withEtOAc. The organic layer was washed with water and brine, dried overMgSO₄, filtered, concentrated, and purified via preparative TLC,affording[3-(4-Methoxy-pyrrolo[2,3-b]pyridin-1-yl)-3-phenyl-propyl]-methyl-amine(123 mg, 21% 3 steps yield). This compound was dissolved in EtOAc, andconverted into the corresponding hydrochloride salt by the addition of 1equivalent of HCl (1 M in Et₂O) to give 107 mg of the corresponding HClsalt.

Example 25

Step 15-[Cyclohexyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione

5-[Cyclohexyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dionewas prepared following the procedure of Example 1 using cyclohexylmagnesium bromide.

Step 23-Cyclohexyl-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide

A mixture of5-[cyclohexyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione(560 mg, 1.57 mmol), pyridine (8 mL) and MeNH₂ (2 M in THF, 16 mL) washeated to 120° C. in sealed vial for 3 h. The reaction was cooled to RTand poured into water. The pH was adjusted to 7. And the resultingsolution was extracted 5 times with EtOAc (100 mL) and 3 times with DCM(200 mL). The organic layers were combined, dried over MgSO₄, filteredand concentrated, affording crude3-Cyclohexyl-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide(270 mg), which was used in the next step without purification.

Step 3[3-Cyclohexyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-methyl-amine

To a RT solution of3-cyclohexyl-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide(170 mg, 0.95 mmol) in THF (10 mL) was added LAH (1 M in THF, 1.5 mL).The mixture was stirred at RT overnight, and an additional LAH (1 M inTHF, 2 mL) was added. The resulting mixture was refluxed for 4 hours andthen quenched by addition of freshly ground Na₂SO₄.10H₂O (3 g).

After stirring for 1 hour, the solids were filtered off and the filtratewas concentrated and purified via preparative HPLC to give[3-Cyclohexyl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propyl]-methyl-amine MSM+H=272.

Example 263-(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine

Step 1 4-Isopropoxy-1H-pyrrolo[2,3-b]pyridine

A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (1.24 g, 8.13 mmol),K(i-Pr)O (3.2 g, 32.5 mmol) and celite (1.9 g) in toluene (150 mL) wasrefluxed for 24 h. The reaction mixture was cooled to 80° C. andquenched by addition of water. The suspension was cooled to RT, andcelite was collected by filtration and triturated with DCM. The filtratewas extracted with chloroform and the combined organic layers were driedonto silica and purified via flash chromatography (hexane/EtOAc),affording 4-Isopropoxy-1H-pyrrolo[2,3-b]pyridine (295 mg, 21% yield).

Step 22-[(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonicacid diethyl ester

2-[(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonicacid diethyl ester was prepared from4-isopropoxy-1H-pyrrolo[2,3-b]pyridine using the procedure of step 1 ofExample 3 (68% yield, 479 mg).

Step 32-[(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonicacid

2-[(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonicacid 100 was prepared from2-[(4-isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonicacid diethyl ester using the procedure of step 2 of Example 3 (80%yield, 335 mg).

Step 4 2-(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-propionicacid

2-(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-propionic acid wasprepared from2-[(4-isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonicacid using the procedure of step 3 of Example 3 (270 mg).

Step 52-(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamide

A mixture of2-(4-isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-propionic acid(270 mg, 0.83 mmol), MeNH₂.HCl (69 mg, 1.04 mmol), TEA (0.43 mL, 3.04mmol), EDCI (199 mg, 1.04 mmol) and HOBt (141 mg, 1.04 mmol) in DCM (50mL) was stirred at RT overnight. The reaction mixture was then washedsuccessively with water (50 mL), 3 times with NaHCO₃ (saturatedsolution, 50 mL), water (50 mL) and brine (50 mL). The organic layer wasdried over MgSO₄, filtered, concentrated, and the pale yellow solidresidue was triturated with Et₂O and hexane to give2-(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamideas a white solid (175 mg, 62% yield).

Step 6[3-(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amine

To a solution of2-(4-isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamide(175 mg, 0.52 mmol) in THF (10 mL) was added LAH (1 M in THF, 1.56 mL).The reaction mixture was refluxed for 24 h, cooled to RT, and quenchedby addition of water (60 μL) and NaOH (1 M, 60 μL) followed by water(180 μL). The organic layer was separated, dried over MgSO₄, filteredand concentrated. The resulting clear oil was acidified with HCl,concentrated to a solid residue, which was triturated with EtOAc and HCl(1M in Et₂O), affording[3-(4-Isopropoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-aminehydrochloride (95 mg).

Example 27[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propyl]-methyl-amine

Step 12-[(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl-methyl]-malonicacid dimethyl ester

To a 0° C. suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.5 g, 3.27mmol) in toluene (15 ml) was added i-PrMgCl (1.5 M in THF, 2.4 ml, 3.60mmol) and stirred at RT for 30 min, after which a solution of2-pyridin-3-yl-methylene-malonic acid dimethyl ester (867 mg, 3.92 mmol)in toluene (4 mL) was added dropwise. The resulting mixture was stirredfor 1 h, quenched by addition of a saturated solution of NH₄Cl. Themixture was diluted with H₂O and extracted twice with EtOAc/MeOH (95/5).The combined organic layers were dried over MgSO₄, filtered andconcentrated. The residue was triturated with a mixture of EtOAc/hexane(3/7) to affording the compound 104 as an off-white solid (746 mg, 61%combined yield).

Step 22-[(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-methyl]-malonicacid

2-[(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-methyl]-malonicacid 105 was prepared from2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl-methyl]-malonicacid dimethyl ester following the procedure of step 2 of Example 3.

Step 3 3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-O-3-pyridin-3-yl-propionicacid

3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propionic acid106 was prepared from2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyridin-3-yl-methyl]-malonicacid following the procedure of step 3 of Example 3 (785 mg).

Step 43-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-pyridin-3-yl-propionamide

3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-pyridin-3-yl-propionamidewas prepared from3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propionic acidfollowing the procedure of step 4 of Example 3 (63% yield, 495 mg).

Step 5[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propyl]-methyl-amine

To a slurry of3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-pyridin-3-yl-propionamide(200 mg, 0.64 mmol) in THF (20 mL) was added BH₃.THF (1 M in THF, 6.4mL). The resulting mixture was refluxed for 45 min, then quenched byaddition of HCl. The reaction mixture was stirred at RT for severalhours until no more gas evolution was observed, it was then basifiedwith KOH (50% in water) and extracted with EtOAc. The organic layer wasseparated, dried over MgSO₄, filtered and concentrated. The residue wasdissolved in isopropanol/Et₂O and HCl (1 M in Et₂O) was added. The whiteprecipitate was collected by filtration under N₂, affording[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-pyridin-3-yl-propyl]-methyl-aminehydrochloride in 56% yield (120 mg).

Example 28 Formulations

Pharmaceutical preparations for delivery by various routes areformulated as shown in the following Tables. “Active ingredient” or“Active compound” as used in the Tables means one or more of theCompounds of Formula I.

Composition for Oral Administration Ingredient % wt/wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration Ingredient % wt/wt. Activeingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration Ingredient Amount Active compound1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 gPropyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation Ingredient % wt/wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation Ingredient % wt/wt. Active ingredient 1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation Ingredients grams Active compound 0.2-2 Span 60 2Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 29 Screening for Human Serotonin Transporter (hSERT) AntagonistsUsing a Scintillation Proximity Assay (SPA)

The screening assay of this example was used to determine the affinityof ligands at the hSERT transporter by competition with [³H]-Citalopram.

Scintillation Proximity Assay (SPA) works by bringing radioligand withinclose proximity to the bead's scintillant to stimulate light emission.In this assay, the receptor-containing membranes were pre-coupled to theSPA beads and the binding of the appropriate radioligand to thetransporter was measured. The light emission was proportional to theamount of bound radioligand. Unbound radioligand produced no signal as aresult of distant proximity to scintillant (lack of energy transfer).

HEK-293 cells (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258)stably expressing recombinant hSERT were maintained with media (DMEMhigh glucose with 10% FBS, 300 μg/ml G418 and 2 mM L-Glutamine) andincubated at 37° C. with 5% CO₂. Cells are released from culture flasksusing PBS for 1-2 minutes. The cells were subsequently centrifuged at1000 g's for 5 minutes and resuspended in PBS prior to being used in themembrane preparation.

Cell membranes were prepared using a membrane preparation buffer of 50mM TRIS (pH 7.4). Cell membranes were prepared from a single cube(7.5×10⁹ cells total). Cells were homogenized using a Polytron (settingmedium for a 4 second burst). The homogenate was then centrifuged at48,000×g for 15 minutes, the supernatant subsequently removed anddiscarded, and the pellet resuspended with fresh buffer. After a secondcentrifugation, the pellet was re-homogenized and brought to a finalvolume determined during the assay. Typically, membrane portions werealiquoted in 3 mg/ml (w:v). and stored at −80° C.

For Scintillation Proximity Assay IC₅₀/K_(i) determination, 50 mMTris-HCl and 300 mM NaCl, (pH 7.4) buffers were utilized. Compounds ofthe invention were diluted from 10 mM to 0.1 nM FAC (10 point curves,whole log/half log dilutions) via a Beckman Biomek 2000 using a serialdilution protocol. The test compounds were then transferred (20 μl/well)and the [³H]-Citalopram radioligand was added at 50 μl/well. Membraneand beads were prepared to a ratio of 10 μg:0.7 mg, with 0.7 mg PVT-WGAAmersham beads (Cat# RPQ0282V) added per well. 130 μl of themembrane:bead mixture was added to the assay plate. The mixtures wereallowed to stand at room temperature for one hour, and were then countedon a Packard TopCount LCS, a generic Scintillation Proximity Assaycounting protocol settings (Energy Range: Low, Efficiency Mode: Normal,Region A: 1.50-35.00, Region B: 1.50-256.00, Count Time (min.): 0.40,Background Subtract: none, Half-Life Correction: no, Quench Indicator:tSIS, Platemap blank subtraction: No, Cross talk reduction: Off).

The % inhibition was calculated for each compound tested [(Compoundcounts per minute (CPM) at maximum concentration-Non-Specific CPM)/TotalCPM*100]. The concentration producing 50% inhibition (IC₅₀) wasdetermined using an iterative non-linear curve fitting technique withActivity Base/Xlfit using the following equation:

$y = {\frac{\max - \min}{1 + \left( {{IC}\; {50/x}} \right)^{n}} + \min}$

where max=total binding, min=non specific binding, x=concentration (M)of the tested compound and n=Hill slope. The inhibition dissociationconstant (Ki) of each compound was determined according to the method ofCheng-Prusoff and then converted into negative logarithm (pKi) of theKi.

Using the above procedure, compounds of the invention were found to haveaffinity for human serotonin transporter. For example,[(S)-3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amineexhibited an IC₅₀ of approximately 8.75 using the above assay.

Example 30 Screening for Compounds Active at Human NorepinephrineTransporter (hNET) Using a Scintillation Proximity Assay (SPA)

This assay was used to determine the affinity of ligands for the hNETtransporter by competition with [³H]-Nisoxetine. As in the hSERT assayof the above example, receptor-containing membranes were pre-coupled tothe SPA beads and the binding of the appropriate radioligand to thetransporter was measured. The light emission was proportional to theamount of bound radioligand, with unbound radioligand producing nosignal.

HEK-293 cells (Tatsumi et al., Eur. J. Pharmacol. 1997, 30, 249-258)stably expressing recombinant hNET (Clone: HEK-hNET #2) were maintainedwith media (DMEM hi glucose with 10% FBS, 300 μg/ml G418 and 2 mML-Glutamine) and incubated at 37° C. with 5% CO₂. Cells were releasedfrom culture flasks using PBS for 1-2 minutes. The cells weresubsequently centrifuged at 1000 g's for 5 minutes and resuspended inPBS prior to being used in the membrane preparation.

Cell membranes were prepared using a membrane preparation buffer of 50mM TRIS (pH 7.4). Cell membranes were prepared from a single cube(7.5×10⁹ cells total). Cells were homogenized using a Polytron (settingmedium for a 4 second burst). The homogenate was then centrifuged at48,000×g for 15 minutes, the supernatant subsequently removed anddiscarded, and the pellet resuspended with fresh buffer. After a secondcentrifugation, the pellet was re-homogenized and brought to a finalvolume determined during the assay. Typically, membrane portions werealiquoted in 3-6 mg/ml (w:v). and stored at −80° C.

³[H]Nisoxetine radioligand (Amersham Cat. # TRK942 or Perkin Elmer Cat.# NET1084, specific activity: 70-87 Ci/mmol, stock concentration:1.22e-5 M, final concentration: 8.25e-9 M), and 50 mM Tris-HCl, 300 mMNaCl, (pH 7.4) buffers were used for Scintillation Proximity AssayIC₅₀/K_(i) determination. Compounds of the invention were diluted from10 mM to 0.1 nM FAC (10 point curves, whole log/half log dilutions) viaa Beckman Biomek 2000 using a serial dilution protocol. The testcompounds were then transferred (20 μl/well) and the radioligand wasadded at 50 μl/well. Membrane and beads were prepared to a ratio of 10μg:0.7 mg, with 0.7 mg PVT-WGA Amersham beads (Cat# RPQ0282V) added perwell. 130 ml of the membrane:bead mixture was added to the assay plate.The mixtures were allowed to stand at room temperature for one hour, andwere then counted on a Packard TopCount LCS, a generic SPA countingprotocol settings (Energy Range: Low, Efficiency Mode: Normal, Region A:1.50-35.00, Region B: 1.50-256.00, Count Time (min.): 0.40, BackgroundSubtract: none, Half-Life Correction: no, Quench Indicator: tSIS,Platemap blank subtraction: No, Cross talk reduction: Off).

The % inhibition was calculated for each compound tested [(Compound CPMat maximum concentration-Non-Specific CPM)/Total CPM*100]. Theconcentration producing 50% inhibition (IC₅₀) was determined using aniterative non-linear curve fitting technique with Activity Base/Xlfitusing the following equation:

$y = {\frac{\max - \min}{1 + \left( {{IC}\; {50/x}} \right)^{n}} + \min}$

where max=total binding, min=non specific binding, x=concentration (M)of the tested compound and n=Hill slope. The inhibition dissociationconstant (Ki) of each compound was determined according to the method ofCheng-Prusoff and then converted into negative logarithm (pKi) of theKi.

Using the above procedure, compounds of the invention were found to haveaffinity for the human norepinephrine transporter. For example,[(S)-3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propyl]-methyl-amineexhibited an IC₅₀ of approximately 7.75 using the above assay.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1-28. (canceled)
 29. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: p is 1 or 2; Aris: pyrrolo[3,2-b]pyridinyl selected from pyrrolo[3,2-b]pyridin-1-yl,pyrrolo[3,2-b]pyridin-2-yl, and pyrrolo[3,2-b]pyridin-3-yl, eachoptionally substituted; R¹ is: (a) aryl selected from phenyl andnaphthyl, each optionally substituted; or (b) heteroaryl selected fromindolyl, pyridinyl, thienyl, furanyl, pyrimidinyl, pyridazinyl,pyrazinyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl,pyrazolyl, quinolinyl and isoquinolinyl, each optionally substituted;(c) optionally substituted arylalkyl; (d) optionally substitutedheteroarylalkyl; (e) cycloalkyl; (f) cycloalkylmethyl; or (g) branchedalkyl; R² is: (a) hydrogen; (b) alkyl; (c) hydroxyalkyl; (d)alkoxyalkyl; (e) benzyl; or or R² is a bond that connects the nitrogenatom to one of the ring carbon atoms of Ar; R³ is: (a) hydrogen; (b)alkyl; (c) hydroxyalkyl; (d) alkoxyalkyl; (e) benzyl; or (f) R² and R³together with the nitrogen to which they are attached may form anoptionally substituted four to seven membered ring that optionallyincludes an additional heteroatom selected from N, O and S; R^(a),R^(b), R^(c) and R^(d) are hydrogen; and: R^(e) is hydrogen or alkyl.30. The compound according to claim 29, wherein p is
 1. 31. The compoundaccording to claim 29, wherein R¹ is aryl, heteroaryl, or cycloalkyl,each of which is optionally substituted.
 32. The compound according toclaim 29, wherein each of R² and R³ is independently hydrogen or alkyl.33. The compound according to claim 29, wherein R² is a bond thatconnects the nitrogen atom to one of the ring carbon atoms of Ar. 34.The compound according to claim 29 of the formula:

or a pharmaceutically acceptable salt thereof, wherein: R² is hydrogen,alkyl, or a bond that connects the nitrogen atom to one of the ringcarbon atoms of Ar; R³ is hydrogen or alkyl; and Ar and R¹ are asrecited in claim
 29. 35. The compound according to claim 34, wherein R¹is phenyl, pyridinyl, or cyclohexyl, each of which is optionallysubstituted.
 36. The compound according to claim 34 of the formula:

wherein m is an integer from 0 to 3; each of R⁴ and R⁵ is independently:hydrogen; alkoxy, cyano, alkyl, halo, —S(O)_(r)R^(f); and—C(═O)NR^(g)R^(h); wherein r is an integer from 0 to 2, and each ofR^(f), R^(g), and R^(h) is independently hydrogen or alkyl; each R⁶ isindependently: alkoxy, cyano, alkyl, amino, alkylamino, dialkylamino,halo, —S(O)_(r)R^(f); and —C(═O)NR^(g)R^(h); wherein r is an integerfrom 0 to 2, and each of R^(f), R^(g), and R^(h) is independentlyhydrogen or alkyl; and R¹, R² and R³ are as recited in claim
 34. 37. Apharmaceutical composition comprising a compound of claim 29 and apharmaceutically acceptable carrier.
 38. A method of treating depressionor anxiety, the method comprising administering an effective amount of acompound of claim 29 to a subject in need thereof.